Methods of treatment with cyp3a4 substrate drugs

ABSTRACT

The present disclosure provides for methods of treating a patient with a CYP3A4 substrate drug, wherein the patient is treated with posaconazole. In some embodiments, the patient stops posaconazole treatment, waits for at least 2 days, and then is treated with the CYP3A4 substrate drug as soon as it is safe to do so. In some embodiments, treatment with the CYP3A4 substrate drug is delayed for about 2-42 days after stopping posaconazole. In some embodiments, the patient is treated with a reduced dose of the CYP3A4 substrate drug for about 2-42 days.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of U.S. application Ser. No.15/596,585, filed May 16, 2017, the entire contents of which areincorporated by reference in its entirety.

BACKGROUND

Posaconazole, also called Noxafil and Posanol, is indicated for theprophylaxis of invasive Aspergillus and Candida infections in patientswho are at high risk of developing these infections due to beingseverely immunocompromised, such as hematopoietic stem cell transplant(HSCT) recipients with graft-versus-host disease (GVHD) or those withhematologic malignancies with prolonged neutropenia from chemotherapy,for the treatment of oropharyngeal candidiasis (OPC), including OPCrefractory (rOPC) to itraconazole and/or fluconazole, the treatment ofinvasive aspergillosis, and the treatment of zygomycosis. Posaconazolehas also been used “off-label” for treating allergic bronchopulmonaryaspergillosis; prophylaxis or treatment of recurrent candidiasis for theesophagus, secondary to HIV infection; Fusarium infections mycosis; andchronic or cavitary necrotizing pulmonary aspergillosis.

Posaconazole is a strong inhibitor of the CYP3A4 enzyme, a member of thecytochrome P450 family of oxidizing enzymes found in the liver. TheseCytochrome P450 enzymes, such as CYP3A4, oxidize small organic moleculesin the body, such as toxins or certain drugs, thereby deactivatingand/or degrading them. Organic molecules in the body (such as a drug)which are primarily oxidized by a particular enzyme can be referred toas “substrates” for the relevant enzyme. A drug which is primarilyoxidized by the CYP3A4 enzyme can be referred to as a “CYP3A4 substratedrug.”

The Noxafil label specifically contraindicates the co-administration ofCYP3A4 substrate drug with specific drugs metabolized by CYP3A4 such assirolimus, CYP3A4 substrates such as pimozide and quinidine, HMG-CoAReductase Inhibitors primarily metabolized through CYP3A4, and ergotalkaloids, and indicates that dosage adjustments should be consideredwhen concomitantly administering posaconazole with other drugsmetabolized by CYP3A4, including Tacrolimus, cyclosporine, vincaalkaloids such as vincristine and vinblastine, and calcium channelblockers such as verapamil, diltiazem, nifedipine, nicardipine, andfelodipine. However, while the Noxafil label does identify specificdrug-drug interactions related to concomitant administration ofposaconazole and CYP3A4 substrate drugs, it does not indicate anyconcerns regarding the administration of CYP3A4 substrate drugs afterceasing the administration of posaconazole.

The present inventors have surprisingly discovered that a delay inadministration of a CYP3A4 substrate drug, or in some instances a doseadjustment of a CYP3A4 substrate drug for a specified time interval isrequired after ceasing the administration of posaconazole in order toprevent or reduce the incidence of dangerous side effects of the CYP3A4substrate drug.

SUMMARY OF THE INVENTION

The present disclosure provides for methods of treating a patient with aCYP3A4 substrate drug contraindicated for concomitant administrationwith a strong CYP3A4 inhibitor, wherein the patient was previouslyadministered a therapeutically effective regimen of posaconazole.

Applicants have discovered that although CYP3A4 substrate drugs aregenerally only contraindicated for coadministration with strong CYP3A4inhibitors, such as posaconazole, CYP3A4 substrate drugs cannot alwaysbe safely administered immediately after a patient has stoppedposaconazole treatment. Applicants have discovered that posaconazoleaccumulation in the body of patients, particularly for specific patientpopulations as described herein, can result in serious and potentiallylife-threatening side effects if a CYP3A4 substrate drug is administeredtoo soon, subsequent to the cessation of a posaconazole regimen.Accordingly, for CYP3A4 substrate drugs, particularly thosecontraindicated for coadministration with a strong CYP3A4 inhibitor(including but not limited to posaconazole), a washout or delay periodof about 2-42 days (e.g., 2-21 days) between ceasing administration ofthe posaconazole regimen and starting administration of the CYP3A4substrate drug is required in order to avoid or reduce the incidence ofside effects resulting from administration of the CYP3A4 substrate drug.Alternatively, rather than delaying administering the CYP3A4 substratedrug after ceasing administration of the posaconazole regimen, in someembodiments, the Applicants have discovered that patients can safely beadministered a reduced dose of the CYP3A4 substrate drug (reducedrelative to the recommended dose of the CYP3A4 substrate drug) for aperiod of time (about 2-42 days (e.g., 2-21 days)) following cessationof the posaconazole regimen, after which the dose of the CYP3A4substrate drug can be safely increased to the recommended level.

In certain embodiments, the disclosed methods of delaying treatment witha CYP3A4 substrate drug, or reducing the dose of a CYP3A4 substratedrug, for about 2-42 days (e.g., 2-21 days) after ceasing administrationof a posaconazole regimen are directed to a normal patient, e.g.,non-obese patients and normal CYP3A4 metabolizers. In certainembodiments, the disclosed methods of delaying treatment of a CYP3A4substrate drug, or reducing the dose of a CYP3A4 substrate drug, forabout 2-42 days (e.g., 2-21 days) after ceasing administration of aposaconazole regimen are directed to patients having specificphysiological characteristics as described herein. Such patients canexhibit a substantially greater exposure to the CYP3A4 substrate drugafter ceasing administration of a posaconazole regimen than waspreviously known, and therefore after ceasing administration ofposaconazole, require substantially longer “washout” periods prior tostarting treatment of a CYP3A4 substrate drug, or require treatment of areduced dose of the CYP3A4 substrate drug for a substantially longerperiod in order to avoid or reduce the incidence of side effectsassociated with treatment of the CYP3A4 substrate drug. Morespecifically, the present applicants have found that patients havingspecific physiological characteristics as described herein exhibithigher than expected exposure to a CYP3A4 substrate drug dosed afterceasing administration of a posaconazole regimen, compared to “normal”patients (e.g., a patient who is otherwise the same except for havingspecific physiological characteristics as described herein). Forexample, patients with e.g., BMI values in the “normal” range (about18.5-24.9) can exhibit substantially reduced CYP3A4 substrate drugelimination; such patients may be described as poor or intermediateCYP3A4 metabolizers. Thus, as disclosed herein, the present inventorshave found that specific patient populations may require substantiallydifferent and longer washout periods after ceasing administration ofposaconazole and prior to starting treatment with a CYP3A4 substratedrug, or alternatively treating with a reduced dose of a CYP3A4substrate drug for a particular period of time after stoppingposaconazole treatment.

In various embodiments, the present disclosure provides for methods oftreating a patient by delaying a first use of a CYP3A4 substrate druguntil about 2-42 days (e.g., 2-21 days) after stopping administration ofposaconazole. In embodiments, the CYP3A4 substrate drug is a drugcontraindicated for concomitant use with a strong CYP3A4 inhibitor, suchas but not limited to posaconazole. Accordingly, in various embodiments,the present disclosure provides for methods of treating a patient whohas previously been treated with multiple doses of posaconazole, with aCYP3A4 substrate drug contraindicated for concomitant treatment with astrong CYP3A4 inhibitor, said method comprising first treating thepatient, or prescribing the first treatment to begin, with a dose of theCYP3A4 substrate drug at least 2-42 days (e.g., 2-21 days) afterstopping a posaconazole treatment.

In various embodiments, the present disclosure provides for methods oftreating a patient, or prescribing the first treatment to begin, with aCYP3A4 substrate drug at a dose which is less than or equal to about 50%of the reference dose, e.g., for a period of at least about 2-42 days(e.g., 2-21 days) after stopping posaconazole treatment. Accordingly, invarious embodiments, the methods include treating, or prescribing thefirst treatment to begin, with a therapeutically effective amount of aCYP3A4 substrate drug contraindicated for concomitant use with a strongCYP3A4 inhibitor to a patient in need thereof. In some embodiments, thepatient has previously been treated with posaconazole. In someembodiments, the patient is treated, or prescribed to be treated, with aCYP3A4 substrate drug at a dose which is no more than about 50% of thereference dose for at least about 2-42 days (e.g., 2-21 days) afterdiscontinuation of the posaconazole regimen.

In some embodiments, after the delay described herein (e.g., at least 2days, including 2-42 days), the CYP3A substrate drug is administered theCYP3A4 substrate drug as soon as it is safe. In some embodiments, theCYP3A4 substrate drug is administered in step (d) as soon as at leastone of the AUC, Cmax, GMR AUC, or GMR Cmax of the CYP3A4 substrate drugdoes not exceed a maximum level where benefits of treating the patientoutweigh risks of elevated exposure to the CYP3A4 substrate drug. Insome embodiments, the maximum level where benefits of treating thepatient outweigh risks of elevated exposure to the CYP3A4 substrate drugis a target safe level listed in Table A. In some embodiments, theCYP3A4 substrate drug is administered to achieve a AUC, Cmax, GMR AUC,or GMR Cmax of the CYP3A4 substrate drug that is above the baseline butdoes not exceed a target safe level listed in Table A for the CYP3A4substrate drug. In some embodiments, the CYP3A4 substrate drug isadministered to achieve an AUC or Cmax of the CYP3A4 substrate drug thatis at least about 105% of a predicted AUC or Cmax for the day on whichthat CYP3A4 substrate drug is administered. In some embodiments, theCYP3A4 substrate drug is administered to achieve an AUC or Cmax of theCYP3A4 substrate drug that is at least about 105% of a predicted AUC orCmax for the day on which that CYP3A4 substrate drug is administered butdoes not exceed a target safe level listed in Table A for the CYP3A4substrate drug. In some embodiments, the CYP3A4 substrate drug isadministered to achieve a GMR AUC or GMR Cmax of the CYP3A4 substratedrug that is at least about 1.05 fold of the expected AUC or Cmax. Insome embodiments, the CYP3A4 substrate drug is administered to achieve aGMR AUC or GMR Cmax of the CYP3A4 substrate drug that is at least about1.05 fold of the expected AUC or Cmax but does not exceed a target safelevel listed in Table A for the CYP3A4 substrate drug.

In some embodiments, the CYP3A4 substrate drug is selected from thegroup consisting of abemaciclib, ivacaftor, olaparib, ruxolitinibphosphate, brexpiprazole, ivacaftor/tezacaftor, regorafenib,daclatasvir, crizotinib, naloxegol oxalate, dabrafenib,elbasvir/grazoprevir, apalutamide, brigatinib, cannabidiol, copanlisib,duvelisib, encorafenib, flibanserin, ivabradine, ivosidenib,panobinostat, sonidegib and vemurafenib.

In some embodiments, the methods providing for treating patients havinga disease or condition selected from the group consisting of:non-metastatic castration-resistant prostate cancer; anaplastic lymphomakinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) whohave progressed on or are intolerant to crizotinib; seizures associatedwith Lennox-Gastaut syndrome or Dravet syndrome in patients 2 years ofage and older; relapsed follicular lymphoma (FL) in adults who havereceived at least two prior systemic therapies; adults with relapsed orrefractory chronic lymphocytic leukemia (CLL) or small lymphocyticlymphoma (SLL) after at least two prior therapies; adult patients withrelapsed or refractory follicular lymphoma (FL) after at least two priorsystemic therapies, in combination with binimetinib; unresectable ormetastatic melanoma with a BRAF V600E or V600K mutation, as detected byan FDA-approved test, the treatment of premenopausal women withacquired, generalized hypoactive sexual desire disorder (HSDD) ascharacterized by low sexual desire that causes marked distress orinterpersonal difficulty and is not due to a co-existing medical orpsychiatric condition, problems within the relationship, or the effectsof a medication or other drug substance, to reduce the risk ofhospitalization for worsening heart failure in patients with stable,symptomatic chronic heart failure with left ventricular ejectionfraction ≤35%, who are in sinus rhythm with resting heart rate ≥70 beatsper minute and either are on maximally tolerated doses of beta-blockersor have a contraindication to beta-blocker use; adult patients withrelapsed or refractory acute myeloid leukemia (AML) with a susceptibleIDH1 mutation as detected by an FDA-approved test; multiple myeloma whohave received at least 2 prior regimens, including bortezomib and animmunomodulatory agent; adult patients with locally advanced basal cellcarcinoma (BCC) that has recurred following surgery or radiationtherapy, or those who are not candidates for surgery or radiationtherapy; unresectable or metastatic melanoma with BRAF V600E mutation asdetected by an FDA-approved test; Erdheim-Chester Disease with BRAF V600mutation; non-metastatic castration-resistant prostate cancer;anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lungcancer (NSCLC) who have progressed on or are intolerant to crizotinib;seizures associated with Lennox-Gastaut syndrome or Dravet syndrome inpatients 2 years of age and older; adult patients with relapsedfollicular lymphoma (FL) who have received at least two prior systemictherapies; adult patients with relapsed or refractory chroniclymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) after atleast two prior therapies; adult patients with relapsed or refractoryfollicular lymphoma (FL) after at least two prior systemic therapies, incombination with binimetinib, for the treatment of patients withunresectable or metastatic melanoma with a BRAF V600E or V600K mutation,as detected by an FDA-approved test; premenopausal women with acquired,generalized hypoactive sexual desire disorder (HSDD) as characterized bylow sexual desire that causes marked distress or interpersonaldifficulty and is not due to a co-existing medical or psychiatriccondition, problems within the relationship, or the effects of amedication or other drug substance; to reduce the risk ofhospitalization for worsening heart failure in patients with stable,symptomatic chronic heart failure with left ventricular ejectionfraction ≤35%, who are in sinus rhythm with resting heart rate ≥70 beatsper minute and either are on maximally tolerated doses of beta-blockersor have a contraindication to beta-blocker use; adult patients withrelapsed or refractory acute myeloid leukemia (AML) with a susceptibleIDH1 mutation as detected by an FDA-approved test; patients withmultiple myeloma who have received at least 2 prior regimens, includingbortezomib and an immunomodulatory agent, the treatment of adultpatients with locally advanced basal cell carcinoma (BCC) that hasrecurred following surgery or radiation therapy, or those who are notcandidates for surgery or radiation therapy; patients with unresectableor metastatic melanoma with BRAF V600E mutation as detected by anFDA-approved test; and the treatment of patients with Erdheim-ChesterDisease with BRAF V600 mutation.

In various embodiments, the present disclosure provides for methods oftreating patients, or prescribing treatment for patients, having adisease or condition selected from the group consisting of schizophreniain adults and adolescents (13 to 17 years), depressive episodesassociated with Bipolar I Disorder (bipolar depression) in adults andpediatric patients (10-17 years) as monotherapy or adjunctive therapywith lithium or valproate, moderate bipolar depression, severe bipolardepression, and severe bipolar depression with acute suicidal idealationand behavior (ASIB), chronic angina, cystic fibrosis in patients 6 yearsand older who are homozygous for the F508del mutation in the CFTR gene,chronic lymphocytic leukemia in patients with 17p deletion, who havereceived at least one prior therapy, unresectable or metastaticliposarcoma or leiomyosarcoma in patients who received a prioranthracycline-containing regimen, advanced or metastatic breast cancerin postmenopausal women with hormone receptor (HR)-positive, humanepidermal growth factor receptor 2 (HER2)-negative advanced ormetastatic breast cancer, negative advanced or metastatic breast cancerin combination with an aromatase inhibitor for postmenopausal women,Duchenne muscular dystrophy (DMD), secondary hyperparathyroidism (HPT)in patients with chronic kidney disease (CKD) on dialysis, hypercalcemiain patients with parathyroid carcinoma or in patients with primary HPTfor who parathyroidectomy would be indicated on the basis of serumcalcium levels, but who are unable to undergo parathyroidectomy,hallucinations and delusions associated with Parkinson's diseasepsychosis, schizophrenia, acute manic or mixed episodes associated withbipolar I disorder, chronic hepatitis C (CHC) infection as a componentof a combination antiviral treatment regimen with peginterferon alfa andribavirin in HCV genotype 1 infected subjects with compensated liverdisease, postmenopausal women with advanced hormone receptor-positive,HER2-negative breast cancer (advanced HR+BC), e.g., in combination withexemestane after failure of treatment with letrozole or anastrozole,progressive neuroendocrine tumors of pancreatic origin (PNET),progressive, well-differentiated, non-functional neuroendocrine tumors(NET) of gastrointestinal (GI) or lung origin that are unresectable,locally advanced or metastatic, advanced renal cell carcinoma (RCC),e.g., after failure of treatment with sunitinib or sorafenib, renalangiomyolipoma and tuberous sclerosis complex (TSC), not requiringimmediate surgery, TSC in patients who have subependymal giant cellastrocytoma (SEGA) that require therapeutic intervention but are notcandidates for surgical resection, type 2 diabetes mellitus in adults asan adjunct to diet and exercise to improve glycemic control, majordepressive disorder (MDD), thrombotic cardiovascular events (e.g.,cardiovascular death, myocardial infarction, or stroke) in patients withacute coronary syndrome (ACS), stroke and systemic embolism in patientswith nonvalvular atrial fibrillation, deep vein thrombosis (DVT), whichmay lead to pulmonary embolism (PE) in patients who have undergone hipor knee replacement surgery, DVT, PE, recurrent DVT and PE followinginitial therapy, moderate to severe active rheumatoid arthritis inpatients who have had inadequate response or tolerance to methotrexate,acute migraine with or without aura, chronic phase and accelerated phasePhiladelphia chromosome positive chronic myeloid leukemia (Ph+ CML) innewly diagnosed patients or in patients resistant to or intolerant toprior therapy that included imatinib, atrial fibrillation (AF) inpatients with a history of paroxysmal or persistant AF or atrial flutter(AFK), who are in sinus rhythm or will be cardioverted, asthma inpatients aged 4 years and older, airflow obstruction and reducingexacerbations in patients with chronic obstructive pulmonary disease,erectile dysfunction (ED), benign prostatic hyperplasia (BPH), pulmonaryarterial hypertension (PAH) (WHO Group 1) to improve exercise ability,gout flares, Familial Mediterranean fever, antiretroviral therapy,anxiety disorders, panic disorders, seizures, insomnia, hypertension,cardiovascular disease, hyperlipidemia, cancer, such as primary kidneycancer, advanced primary liver cancer, radioactive iodine resistantadvanced thyroid carcinoma, renal cell carcinoma, imatinib-resistantgastrointestinal stromal tumor, mantle cell lymphoma in patients whohave received at least one prior therapy, chronic lymphocyticleukemia/small lymphocytic lymphoma, chronic lymphocytic leukemia/smalllymphocytic lymphoma with 17p deletion, Waldenström's macroglobulinemia,marginal zone lymphoma who require systemic therapy and have received atleast one prior anti-CD20-based therapy, unresectable or metastaticmelanoma with a BRAF V600E or V600K mutation, allergies,transplantation, hormone-refractory metastatic prostate cancerpreviously treated with a docetaxel-containing treatment regimen,hormone-refractory metastatic prostate cancer previously treated with adocetaxel-containing treatment regimen, treatment of clinicallysignificant hypervolemic and euvolemic hyponatremia, including patientswith heart failure and Syndrome of Inappropriate Antidiuretic Hormone(SIADH), prevention of acute and delayed nausea and vomiting associatedwith initial and repeat courses of highly emetogenic cancer chemotherapy(HEC) including high-dose cisplatin, prevention of delayed nausea andvomiting associated with initial and repeat courses of moderatelyemetogenic cancer chemotherapy (MEC), over-active bladder with symptomsof urge urinary incontinence, urgency, and urinary frequency, metastaticnon-small cell lung cancer (NSCLC) whose tumors have epidermal growthfactor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitutionmutations as detected by an FDA-approved test receiving first-line,maintenance, or second or greater line treatment after progression,locally advanced, unresectable or metastatic pancreatic cancer, incombination with gemcitabine, HER2-positive, metastatic breast cancerwho previously received trastuzumab and a taxane, separately or incombination in patients who have either: received prior therapy formetastatic disease or developed disease recurrence during or within sixmonths of completing adjuvant therapy, chronic, accelerated, or blastphase Ph+ chronic myelogenous leukemia (CML) in adults with resistanceor intolerance to prior therapy, gastrointestinal stromal tumor (GIST)after disease progression on or intolerance to imatinib mesylate,advanced renal cell carcinoma (RCC), progressive, well-differentiatedpancreatic neuroendocrine tumors (pNET) in patients with unresectablelocally advanced or metastatic disease, CCR5-tropic HIV-1 infection inpatients 2 years of age and older weighing at least 10 kg in combinationwith other antiretroviral agents, advanced renal cell carcinoma,advanced soft tissue sarcoma who have received prior chemotherapy, manicand mixed episodes associated with Bipolar I, Major Depressive Disorder,irritability associated with Autistic Disorder, Tourette's disorder,agitation associated with schizophrenia or bipolar mania, advanced renalcell carcinoma after failure of one prior systemic therapy, to improveglycemic control in adults with type 2 diabetes mellitus (T2DM) who haveinadequate control with dapagliflozin or who are already treated withdapagliflozin and saxagliptin, progressive, metastatic medullary thyroidcancer (MTC), advanced renal cell carcinoma (RCC) who have receivedprior anti-angiogenic therapy, chronic phase, accelerated phase, orblast phase chronic myeloid leukemia (CML) or Ph+ ALL in adults for whomno other tyrosine kinase inhibitor (TKI) therapy is indicated,T315I-positive CML (chronic phase, accelerated phase, or blast phase) orT315I-positive Philadelphia chromosome in adults, positive acutelymphoblastic leukemia (Ph+ ALL), invasive aspergillosis, invasivemucormycosis, to reduce low-density lipoprotein cholesterol (LDL-C),total cholesterol (TC), apolipoprotein B (apo B), and non-high densitylipoprotein cholesterol (non-HDL-C) in patients with homozygous familialhypercholesterolemia (HoFH), schizophrenia in adults, hormone receptor(HR)-positive, human epidermal growth factor receptor 2 (HER2)-negativeadvanced or metastatic breast cancer in combination with an aromataseinhibitor as initial endocrine based therapy in postmenopausal women, orfulvestrant in women with disease progression following endocrinetherapy, Major Depressive Disorder (MDD), suppression of motor andphonic tics in patients with Tourette's Disorder who have failed torespond satisfactorily to standard treatment, treatment of multiplemyeloma in patients who have received at least two prior therapiesincluding lenalidomide and a proteasome inhibitor and have demonstrateddisease progression on or within 60 days of completion of the lasttherapy, non-small cell lung cancer (NSCLC) whose disease has notprogressed after four cycles of platinum-based first-line chemotherapy,locally advanced or metastatic NSCLC after failure of at least one priorchemotherapy regimen, locally advanced, unresectable or metastaticpancreatic cancer, overactive bladder with symptoms of urge urinaryincontinence, urgency, and urinary frequency, advanced renal cellcarcinoma (RCC) after failure of treatment with sunitinib or sorafenib,subependymal giant cell astrocytoma (SEGA) associated with tuberoussclerosis (TS) who require therapeutic intervention but are notcandidates for curative surgical resection, renal angiomyolipoma,tuberous sclerosis complex, hormone receptor (HR)-positive, humanepidermal growth factor receptor 2 (HER2)-negative advanced ormetastatic breast cancer with disease progression following endocrinetherapy in women in combination with fulvestrant, as monotherapy for thetreatment of adult patients with HRpositive, HER2-negative advanced ormetastatic breast cancer with disease progression following endocrinetherapy and prior chemotherapy in the metastatic setting, cysticfibrosis (CF) in patients age 2 years and older who have one mutation inthe CFTR gene that is responsive to ivacaftor based on clinical and/orin vitro assay data, deleterious or suspected deleterious germlineBRCA-mutated advanced ovarian cancer in adult patients who have beentreated with three or more prior lines of chemotherapy, intermediate orhigh-risk myelofibrosis, including primary myelofibrosis,post-polycythemia vera myelofibrosis and post-essential thrombocythemiamyelofibrosis, polycythemia vera patients who have had an inadequateresponse to or are intolerant of hydroxyurea, as an adjunctive therapyto antidepressants for the treatment of major depressive disorder (MDD),schizophrenia, cystic fibrosis (CF) patients aged 12 years and older whoare homozygous for the F508del mutation or who have at least onemutation in the cystic fibrosis transmembrane conductance regulator(CFTR) gene that is responsive to tezacaftor/ivacaftor based on in vitrodata and/or clinical evidence, metastatic colorectal cancer (CRC)patients who have been previously treated with fluoropyrimidine-,oxaliplatin- and irinotecan-based chemotherapy, an antiVEGF therapy,and, if RAS wild-type, an anti-EGFR therapy, locally advanced,unresectable or metastatic gastrointestinal stromal tumor (GIST)patients who have been previously treated with imatinib mesylate andsunitinib malate, hepatocellular carcinoma (HCC) who have beenpreviously treated with sorafenib, chronic HCV genotype 1 or 3 infectionwith sofosbuvir and with or without ribavirin, metastatic non-small celllung cancer (NSCLC) in patients whose tumors are anaplastic lymphomakinase (ALK) or ROS1-positive as detected by an FDA-approved test,opioid induced constipation (OIC) in adult patients with chronicnon-cancer pain, including patients with chronic pain related to priorcancer or its treatment who do not require frequent (e.g., weekly)opioid dosage escalation, unresectable or metastatic melanoma inpatients with BRAF V600E mutation as detected by an FDA-approved test,in combination with trametinib, for the treatment of unresectable ormetastatic melanoma in patients with BRAF V600E or V600K mutations asdetected by an FDA-approved test, melanoma in patients with BRAF V600Eor V600K mutations, as detected by an FDA-approved test, and involvementof lymph node(s), following complete resection, metastatic non-smallcell lung cancer (NSCLC) in patients with BRAF V600E mutation asdetected by an FDA-approved test, locally advanced or metastaticanaplastic thyroid cancer (ATC) in patients with BRAF V600E mutation andwith no satisfactory locoregional treatment options, with or withoutribavirin for treatment of chronic HCV genotypes 1 or 4 infection inadults, the treatment of patients with non-metastaticcastration-resistant prostate cancer, the treatment of patients withanaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lungcancer (NSCLC) who have progressed on or are intolerant to crizotinib,the treatment of seizures associated with Lennox-Gastaut syndrome orDravet syndrome in patients 2 years of age and older, the treatment ofadult patients with relapsed follicular lymphoma (FL) who have receivedat least two prior systemic therapies, the treatment of adult patientswith relapsed or refractory chronic lymphocytic leukemia (CLL) or smalllymphocytic lymphoma (SLL) after at least two prior therapies, thetreatment of adult patients with relapsed or refractory follicularlymphoma (FL) after at least two prior systemic therapies, incombination with binimetinib, for the treatment of patients withunresectable or metastatic melanoma with a BRAF V600E or V600K mutation,as detected by an FDA-approved test, the treatment of premenopausalwomen with acquired, generalized hypoactive sexual desire disorder(HSDD) as characterized by low sexual desire that causes marked distressor interpersonal difficulty and is not due to a co-existing medical orpsychiatric condition, problems within the relationship, or the effectsof a medication or other drug substance, to reduce the risk ofhospitalization for worsening heart failure in patients with stable,symptomatic chronic heart failure with left ventricular ejectionfraction ≤35%, who are in sinus rhythm with resting heart rate ≥70 beatsper minute and either are on maximally tolerated doses of beta-blockersor have a contraindication to beta-blocker use, the treatment of adultpatients with relapsed or refractory acute myeloid leukemia (AML) with asusceptible IDH1 mutation as detected by an FDA-approved test, thetreatment of patients with multiple myeloma who have received at least 2prior regimens, including bortezomib and an immunomodulatory agent, thetreatment of adult patients with locally advanced basal cell carcinoma(BCC) that has recurred following surgery or radiation therapy, or thosewho are not candidates for surgery or radiation therapy, the treatmentof patients with unresectable or metastatic melanoma with BRAF V600Emutation as detected by an FDA-approved test, and the treatment ofpatients with Erdheim-Chester Disease with BRAF V600 mutation.

In some embodiments, the methods include treating the disease orcondition with a CYP3A4 substrate drug which is contraindicated forconcomitant use with a strong CYP3A4 inhibitor, wherein the patient isalso in need of treatment with a strong CYP3A4 inhibitor (i.e.,posaconazole). In some embodiments, the methods include (a) delaying afirst treatment of the CYP3A4 substrate drug for at least about 2-42days after stopping posaconazole; and then (b) treating, or prescribinga first treatment, with the CYP3A4 substrate drug. In other embodiments,the methods include (a) delaying a first treatment of the CYP3A4substrate drug for at least about 2-21 days after stoppingadministration of the posaconazole regimen, and then (b) treating orprescribing a first treatment the CYP3A4 substrate drug at a dose whichis less than or equal to about 50% of the reference dose for at leastabout 2-42 days after stopping administration of the posaconazoleregimen.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows mean (±standard error) plasma posaconazole concentrationsin normal-weight subjects, and in obese subjects during the period ofposaconazole administration and after disconcontinuation. See Table 2for kinetic analysis.

FIG. 2 shows mean plasma lurasidone concentrations in normal-weightsubjects (FIGS. 2A and 2B) and in obese subjects (FIGS. 2C and 2D).FIGS. 2A and 2C show the 72-hour duration of the study with alogarithmic concentration axis. FIGS. 2B and 2D show the first 24 hoursafter dosage with a linear concentration axis. (Data for Days 20 and 26is not shown).

FIG. 3 shows the arithmetic mean (±standard error) ratio of lurasidoneAUC during and after posaconazole dosage divided by the AUC in thebaseline control condition in normal-weight and obese subject groups. Atall time points, the ratios were significantly different from 1.0.

FIG. 4 shows the relation of plasma posaconazole concentration (X-axis)to lurasidone AUC (Y-axis). Solid line represents the function of bestfit as determined by linear regression analysis. The fitted function is:Y=2.38 X^(0.58)+110.6.

FIG. 5 shows the mean (±SD) and log-transformed plasma posaconazoleconcentrations in normal-weight subjects and obese subjects during theperiod of posaconazole administration and after discontinuation. FIG. 5Ashows a linear concentration axis. FIG. 5B shows a logarithmicconcentration axis.

FIG. 6 shows the mean (±SD) plasma ranolazine concentrations innormal-weight subjects (FIG. 6A) and obese subjects (FIG. 6B) alone (day1), with posaconazole coadministration (day 15), and after posaconazolediscontinuation (days 18-29). See Table 10 for kinetic analysis. Top islinear concentration axes. Bottom is logarithmic concentration axes.

FIG. 7 shows the geometric mean ratios (GMR) and 90% CI of ranolazineAUC (FIG. 7A) and Cmax (FIG. 7B) relative to day 1. GMR=1.5 line refersto the levels observed during ranolazine coadministration with diltiazemin preapproval studies. AUC indicates area under the concentration-timecurve; Cmax, peak concentration.

FIG. 8 shows actual lurasidone AUC ratios measured for normal-weight andobese subjects (dashed lines) compared to lurasidone AUC for thepatients that would have been predicted from posaconazole half-life(expected lurasidone AUC ratios; solid line).

FIG. 9 shows actual ranolazine AUC ratios measured for normal-weight andobese subjects (dashed lines) compared to ranolazine AUC for thepatients that would have been predicted from posaconazole half-life(expected ranolazine AUC ratios; solid line).

FIG. 10 shows the predicted decay curve for encorafenib (solid line) anda maximum (“target safe level”) GMR of AUC level to be achieved by themethods disclosed herein.

DETAILED DESCRIPTION

All documents, including patents, applications, and non-patentpublications cited herein are incorporated herein in their entiretiesfor all purposes.

As used herein, the term “about” refers to an amount somewhat more orless than the stated parameter value, for example plus or minus five orten percent of the object that “about” modifies, or as one of skill inthe art would recognize from the context (e.g., approximately 50% of theinterval between values). The term “about” also includes the valuereferenced. For example, a BMI of about 40 includes 40, as well asvalues somewhat below or above 40.

As used herein, the term “patient” refers to a human subject. In someembodiments, the patient can be a male or a female. In some embodiments,the patient can be an adult, or a pediatric patient.

As used herein “treating or “prescribing” as it pertains to the CYP3A4substrate drug during the 2-42 day period after ceasing posaconazoletreatment, refers to the overall therapeutic regimen of the CYP3A4substrate drug. For example, a patient may be prescribed or administered(including self-administering) a reduced dose of the CYP3A4 substratedrug (e.g., no more than about 50% of the reference dose of the CYP3A4substrate drug) during this period. In some embodiments, the patientwould not be administered, or would, in the physician's prescribeddosing regimen, be advised not to take the CYP3A4 substrate drug duringthe 2-42 day period; afterwards, the patient could (or would beprescribed to) resume taking e.g., the reference amount of the CYP3A4substrate drug.

As used herein, the terms “treating,” “treatment” and “treat” include(i) preventing a particular disease or disorder from occurring in asubject who may be predisposed to the disease or disorder but has notyet been diagnosed as having it; (ii) curing, treating, or inhibitingthe disease, i.e., arresting its development; or (iii) ameliorating thedisease by reducing or eliminating symptoms, conditions, and/or bycausing regression of the disease. In some embodiments, “treating,”“treatment” and “treat” may include administering a therapeuticallyeffective regimen as defined herein.

As used herein, a “therapeutically effective regimen” refers to atreatment regimen of a duration and dosage sufficient to treat a diseaseor condition for which a drug is prescribed.

As used herein, a “patient” refers to human subject that has anindication amenable to treatment with posaconazole and is also in needof treatment with a CYP3A4 substrate drug. For example, the patient,prior to being treated with or prescribed posaconazole, cansimultaneously have a first indication amenable to treatment withposaconazole and a second indication amenable to treatment the CYP3A4substrate drug. In some such embodiments, the patient is first treatedwith posaconazole, and then, after stopping the posaconazole regimen,the patient is switched to a treatment described herein for the CYP3A4substrate drug. In other embodiments, the patient, while being treatedwith posaconazole, develops an indication amenable to treatment with aCYP3A4 substrate drug. In some such embodiments, after stopping theposaconazole regimen, the patient is switched to a treatment descriedherein for the CYP3A4 substrate drug. As used herein, a “patient” doesnot include a subject that, at some point after stopping posaconazoletreatment, subsequently develops an indication which is amenable totreatment with a CYP3A4 substrate drug.

As used herein, a “patient treated with posaconazole” or a “patientpreviously on posaconazole” refers to a patient having an indicationwhich was amenable to treatment with posaconazole.

As used herein, the term “normal baseline C_(max)” or “baseline C_(max)”refers to the average C_(max) of a drug measured at the same dosage inan otherwise identical patient population that was not previouslytreated with the strong CYP3A4 inhibitor (e.g., posaconazole). Forexample, when the CYP3A4 substrate drug is ranolazine, the “normalbaseline C_(max)” of ranolazine refers to the average C_(max) ofranolazine measured at the same dosage of ranolazine in an otherwiseidentical patient population that was not previously treated with thestrong CYP3A4 inhibitor (e.g., posaconazole). As another example, whenthe CYP3A4 substrate drug is lurasidone, the “normal baseline C_(max)”of lurasidone refers to the average C_(max) of lurasidone measured atthe same dosage of lurasidone in an otherwise identical patient whichwas not previously treated with the strong CYP3A4 inhibitor (e.g.,posaconazole). As another example, when the CYP3A4 substrate drug istadalafil, the “normal baseline C_(max)” of tadalafil refers to theaverage C_(max) of tadalafil measured at the same dosage of tadalafil inan otherwise identical patient which was not previously treated with thestrong CYP3A4 inhibitor (e.g., posaconazole).

As used herein, the term “normal baseline AUC” or “baseline AUC” refersto the average AUC of a drug measured at the same dosage in an otherwiseidentical patient population that was not previously treated with thestrong CYP3A4 inhibitor (e.g., posaconazole). For example, when theCYP3A4 substrate drug is ranolazine, the “normal baseline AUC” ofranolazine refers to the average AUC of ranolazine measured at the samedosage of ranolazine in an otherwise identical patient population thatwas not previously treated with the strong CYP3A4 inhibitor (e.g.,posaconazole). As another example, when the CYP3A4 substrate drug islurasidone, the “normal baseline AUC” of lurasidone refers to theaverage AUC of lurasidone measured at the same dosage of lurasidone inan otherwise identical patient population that was not previouslytreated with the strong CYP3A4 inhibitor (e.g., posaconazole). Asanother example, when the CYP3A4 substrate drug is tadalafil, the“normal baseline AUC” of tadalafil refers to the average AUC oftadalafil measured at the same dosage of tadalafil in an otherwiseidentical patient population that was not previously treated with thestrong CYP3A4 inhibitor (e.g., posaconazole).

As used herein, “normal,” “reference,” or other derivations orvariations thereof refers to a non-obese state in a person who can haveat least one of the following characteristics: BMI less than about 35, %IBW less than about 150%, waist size less than about 42, % body fat lessthan about 40%, % android body fat less than about 40%, % gynoid bodyfat less than about 40%, and total body fat less than about 40 kg.Unless otherwise modified “normal metabolizer” also means an extensiveCYP3A4 metabolizer.

As used herein, a “reference dose” refers to the dosage of a particularCYP3A4 substrate drug, as indicated on the manufacture's FDA-approvedlabel (e.g., the most recent FDA-approved label for the particularCYP3A4 drug in effect as of Nov. 14, 2018, prescribed for an identicalpatient not previously treated with the strong CYP3A4 inhibitor (e.g.,posaconazole). It is common for a particular drug to be approved formultiple different indications, and each indication may have a differentreference dose. Similarly, drugs are commonly approved for different agegroups, and each age group may have a different reference dose. In someembodiments, the reference dose is selected based on the patient's ageand condition. Furthermore, some drug labels may recommend a range ofdoses to treat a particular indication; however, for an individualpatient, a specific dose within the recommended range will be safe andtherapeutically effective. In such embodiments, the safe andtherapeutically effective dose for a particular patient is the“reference dose” for that patient. Specific reference doses for CYP3A4substrate drugs are provided herein.

Any reference to a CYP3A4 substrate drug herein also encompasses all ofthe pharmaceutically acceptable isomers (e.g., stereoisomers), solvates,hydrates, polymorphs, salts, and prodrugs (e.g., esters and phosphates).For example, a reference to solifenacin herein also includes itspharmaceutically acceptable salts, such as a succinate salt. As anotherexample, a reference to naloxegol herein also includes itspharmaceutically acceptable salts, such as an oxalate salt. As anotherexample, a reference to aripiprazole herein also includes itspharmaceutically acceptable prodrugs, such as aripiprazole lauroxil.

As used herein, “stereoisomer” is a general term used for all isomers ofindividual molecules that differ only in the orientation of their atomsin space. The term stereoisomer includes mirror image isomers(enantiomers), mixtures of mirror image isomers (racemates, racemicmixtures), geometric (cis/trans or E/Z) isomers, and isomers ofcompounds with more than one chiral center that are not mirror images ofone another (diastereoisomers). The CYP3A4 substrate drugs of thepresent invention may have asymmetric centers and occur as racemates,racemic mixtures, individual diastereoisomers, or enantiomers, or mayexist as geometric isomers, with all isomeric forms of said compoundsbeing included in the present invention. Further, the CYP3A4 substratedrug may include any ratio for a mixture of stereoisomers, e.g., fromabout 1:99 to about 99:1 includuing all ratios and subranges in between,such as about 95:5, about 90:10, about 85:15, about 80:20, about 75:25,about 70:30, about 65:35, about 60:40, about 55:45, about 50:50, about45:55, about 40:60, about 35:65, about 30:70, about 25:75, about 20:80,about 15:85, about 10:90, and about 95:5.

The present disclosure also encompasses combinations of the CYP3A4substrate drugs described herein. Therefore, in accordance of any of theembodiments of the present disclosure, a patient may be treated withmore than one CYP3A4 substrate drug, such as lurasidone and ranolazine.

Disclosed herein are methods of treating, or prescribing treatment for,a patient with a CYP3A4 substrate drug contraindicated for concomitantadministration with a strong CYP3A4 inhibitor, wherein the patient waspreviously treated with posaconazole, particularly when patients havingone or more of the physiological characteristics described herein aresubsequently treated with a CYP3A4 substrate drug. That is, thedisclosure provides for methods of treating different patientpopulations—e.g., “normal” patients, obese patients, and/or intermediateor worse (e.g., poor) CYP3A4 metabolizers—with a CYP3A4 substrate drugcontraindicated for concomitant administration with a strong CYP3A4inhibitor after said patient has ceased posaconazole treatment. Methodsof initiating treatment with a CYP3A4 substrate drug intended to treatvarious conditions or disorders in patients previously treated withposaconazole are also described herein. The present disclosure alsoprovides methods of preventing or decreasing the risk of side effectsassociated with overexposure to a CYP3A4 substrate drug in normalpatients, obese patients and/or patients with impaired CYP3A4 function(e.g., poor or intermediate CYP3A4 metabolizers) and who had previouslybeen treated with a posaconazole regimen prior to treating orprescribing a CYP3A4 substrate drug to said patient. (including thosefor treating conditions described herein).

In various embodiments, the present disclosure provides methods fortreating, or prescribing treatment for, a patient who had been treatedwith a therapeutically effective posaconazole regimen with a CYP3A4substrate drug, after a “washout” period of about 2-42 days afterceasing administration of posaconazole. This washout period allows forthe blood plasma concentrations of posaconazole to be reduced toappropriate levels after which a CYP3A4 substrate drug can beadministered without creating an elevated risk of serious side effectsfrom the CYP3A4 substrate drug. As described herein, the presentApplicants have found that CYP3A4 substrate drugs can be safelyadministrated to a patient previously treated with posaconazole, byfirst treating, or prescribing a first treatment, with the CYP3A4substrate drug (i.e., initiating the treatment with the CYP3A4 substratedrug) following a “washout” period of about 2-42 days starting at thetime the patient has stopped posaconazole treatment. However, the needfor such a washout period has been hitherto unknown, as such CYP3A4substrate drugs are conventionally contraindicated for concomitantadministration with posaconazole. As also described herein, in someembodiments the present Applicants have found that instead of a washoutperiod, the CYP3A4 substrate drug can potentially be safelyadministrated to a patient previously treated with posaconazole, at adose which is no more than about 50% of the reference dose of the CYP3A4substrate drug for a period of about 2-42 days after ceasing theposaconazole treatment. Similarly, such a dosing regime has beenhitherto unknown.

Cytochrome P450 3A4 (CYP3A4) is an enzyme that modifies small organicmolecules, such as particular drugs (specifically including drugsreferred to herein as “CYP3A4 substrate drugs”), so that the moleculesare metabolized and eliminated from the body. Some substances, termed“CYP3A4 inhibitors,” reduce the activity of the CYP3A4 enzyme, andtherefore these CYP3A4 inhibitors can increase the exposure of a patientto CYP3A4 substrate drugs. Strong CYP3A4 inhibitors can deactivateCYP3A4 if administered in an appropriate dose, which can result inexcessive and potentially dangerous blood plasma levels of aconcomitantly administered CYP3A4 substrate drugs. Consequently,concomitant administration of CYP3A4 substrate drugs is contraindicatedwith strong CYP3A4 inhibitors.

As used herein, a “strong CYP3A4 inhibitor” refers to a drug deemed soby the FDA and/or which causes at least about a 5-fold increase in theAUC of a sensitive CYP3A4 substrate drug, or more than about an 80%decrease in the clearance of a sensitive CYP3A4 substrate drug. Themethods disclosed herein can be applied to treat a patient with anyCYP3A4 substrate drug which is contraindicated for concomitantadministration with any strong CYP3A4 inhibitor, wherein the patient hasbeen treated with a strong CYP3A4 inhibitor, such as posaconazole.

Co-administration of posaconazole and CYP3A4 substrate drugs known toprolong the QTc interval are contraindicated. The presence ofconcomitant and clinically significant plasma levels of posaconazole andsuch CYP3A4 substrate drugs can result in significantly elevated levelsof the CYP3A4 substrate drug, which creates a risk of prolonging QT.Consequences of prolonged QT include arrhythmias, rapid heartbeat,abnormal heart rhythm, heart palpitations, dizziness, lightheadedness,sudden fainting, seizure, torsades de pointes, and cardiac death.

For example, according to the drug label for posaconazole (NOXAFIL®label, revised 09/2016), patients are advised not to co-administerspecific CYP3A4 substrate drugs such as serolimus, pimozide, quinidine,HMG-CoA reductase inhibitors, ergot alkaloids, or drugs known to prolongthe QTc interval and cause cases of TdP, with posaconazole. The NOXAFIL®label also warns that dose adjustments should be considered forconcomitant administration of posaconazole and other drugs metabolizedby CYP3A4 such as tacrolimus, cyclosporine, vinca alkaloids, and calciumchannel blockers. However, the drug label of posaconazole does notrecognize that any washout period or any stratification of the patientpopulations are required after ceasing administration of posaconazoleand before initiating administration of a CYP3A4 substrate.

In some embodiments, the strong CYP3A4 inhibitor is posaconazole (i.e.,Noxafil, Posanol). Posaconazole is currently formulated as an oralsuspension solution (40 mg/mL), and intravenous solution (18 mg/mL), anddelayed release tablets (100 mg). According to the drug label (Merck &Co., Inc.,), current recommended dosing levels for prophylaxis ofinvasive Aspergillus and Candida infections by intraveneous injection orby delayed-release tablet are 300 mg twice a day on the first day and300 mg once a day thereafter, or 200 mg three times a day by oralsuspension. Current recommended dosing levels for treatment oforopharyngeal candidiasis by oral suspension are 100 mg twice a day onthe first day and 100 mg once a day for 13 days. Current recommendeddosing levels for treatment of oropharyngeal candidiasis refractory toitraconazole and/or fluconazole by oral suspension is 400 mg twice aday.

In some embodiments, posaconazole can be indicated for the treatment offungal infections. In one embodiment, posaconazole can be indicated forthe treatment of infections caused by Candida, e.g., oropharyngealcandidiasis. In one embodiment, posaconazole can be indicated for thetreatment of oropharyngeal candidiasis which is refractory toitraconazole and/or fluconazole. In one embodiment, posaconazole can beindicated for the treatment of infections caused by Aspergillus. In oneembodiment, posaconazole can be indicated for the treatment ofinfections caused by Zygomycetes. In some embodiments, posaconazole canbe indicated for the prophylaxis of Aspergillus or Candida infections,e.g., in immunocompromised patients at high risk of developing suchinfections, such as hematopoietic stem cell transplant (HSCT) recipientswith graft-versus-host disease (GVHD) or patients with hematologicmalignancies with prolonged neutropenia from chemotherapy. In oneembodiment, posaconazole can be indicated for the treatment ofzygomycosis. In one embodiment, posaconazole can be indicated for thetreatment of allergic bronchopulmonary aspergillosis. In one embodiment,posaconazole can be indicated for the treatment or prophylaxis ofrecurrent candidiasis for the esophagus, secondary to HIV infections. Inone embodiment, posaconazole can be indicated for the treatment ofFusarium infections mycosis. In one embodiment, posaconazole can beindicated for the treatment of and chronic or cavitary necrotizingpulmonary aspergillosis.

As used herein, a “CYP3A4 substrate drug” refers to any drug which isprimarily metabolized by the CYP3A4 enzyme which is administered in anypharmaceutically acceptable formulation (e.g. tablet, capsule, oralsolution, injection, infusion, or delayed or extended releaseformulations thereof). In some embodiments, the CYP3A4 drug islurasidone (Latuda). In some embodiments, the CYP3A4 is ranolazine(Ranexa). In some embodiments, the CYP3A4 substrate drugs can includelumacaftor/ivacaftor (Orkambi). In some embodiments, the CYP3A4substrate drugs can include venetoclax (Venclexta). In some embodiments,the CYP3A4 substrate drugs can include trabectedin (Yondelis). In someembodiments, the CYP3A4 substrate drugs can include ribociclib succinate(Kisqali). In some embodiments, the CYP3A4 substrate drugs can includedeflazacort (Emflaza). In some embodiments, the CYP3A4 substrate drugscan include cinacalcet hydrochloride (Sensipar). In some embodiments,the CYP3A4 substrate drugs can include pimavanserin tartrate (Nuplazid).In some embodiments, the CYP3A4 substrate drugs can include aripiprazolelauroxil (Aristada). In some embodiments, the CYP3A4 substrate drugs caninclude cariprazine hydrochloride (Vraylar). In some embodiments, theCYP3A4 substrate drugs can include simeprevir sodium (Olysio). In someembodiments, the CYP3A4 substrate drugs can include everolimus(Afinitor, Afinitor Disperz, Zortress). In some embodiments, the CYP3A4substrate drugs can include saxagliptin hydrochloride (Onglyza). In someembodiments, the CYP3A4 substrate drugs can includesaxagliptin/metformin hydrochloride (Kombiglyze XR). In someembodiments, the CYP3A4 substrate drugs can include ticagrelor(Brilinta). In some embodiments, the CYP3A4 substrate drugs can includevilazodone hydrochloride (Viibryd). In some embodiments, the CYP3A4substrate drugs can include apixaban (Eliquis). In some embodiments, theCYP3A4 substrate drugs can include tofacitinib citrate (Xeljanz). Insome embodiments, the CYP3A4 substrate drugs can include eletriptanhydrobromide (Relpax). In some embodiments, the CYP3A4 substrate drugscan include nilotinib hydrochloride monohydrate (Tasigna). In someembodiments, the CYP3A4 substrate drugs can include dronedaronehydrochloride (Multaq). In some embodiments, the CYP3A4 substrate drugscan include fluticasone propionate/salmeterol xinafoate (Advair Diskus).In some embodiments, the CYP3A4 substrate drugs can include rivaroxaban(Xarelto). In some embodiments, the CYP3A4 substrate drugs can includetadalafil (Cialis, Adcirca). In some embodiments, the CYP3A4 substratedrugs can include colchicine (Colcrys). In some embodiments, the CYP3A4substrate drugs can include ibrutinib (Imbruvica). In some embodiments,the CYP3A4 substrate drugs can include cobimetinib (Cotellis). In someembodiments, the CYP3A4 substrate drugs can include cabazitaxel(Jevtana). In some embodiments, the CYP3A4 substrate drugs can includetolvaptan (Samsca). In some embodiments, the CYP3A4 substrate drugs caninclude fosaprepitant dimeglumine (Emend). In some embodiments, theCYP3A4 substrate drugs can include aprepitant (Emend). In someembodiments, the CYP3A4 substrate drugs can include solifenacinsuccinate (VESIcare). In some embodiments, the CYP3A4 substrate drugscan include erlotinib hydrochloride (Tarceva). In some embodiments, theCYP3A4 substrate drugs can include ado-trastuzumab ematansine(Kadcycla). In some embodiments, the CYP3A4 substrate drugs can includebosutinib monohydrate (Bosulif). In some embodiments, the CYP3A4substrate drugs can include sunitinib malate (Sutent). In someembodiments, the CYP3A4 substrate drugs can include fesoterodinefumarate (Toviaz). In some embodiments, the CYP3A4 substrate drugs caninclude maraviroc (Selzentry). In some embodiments, the CYP3A4 substratedrugs can include pazopanib hydrochloride (Votrient). In someembodiments, the CYP3A4 substrate drugs can include aripiprazole(Abilify). In some embodiments, the CYP3A4 substrate drugs can includeaxitinib (Inlyta). In some embodiments, the CYP3A4 substrate drugs caninclude dapagliflozin/saxagliptin (Farxiga/Onglyza). In someembodiments, the CYP3A4 substrate drugs can include cabozantinibS-malate (Cabometyx). In some embodiments, the CYP3A4 substrate drugscan include ponatinib hydrochloride (Iclusig). In some embodiments, theCYP3A4 substrate drugs can include isavuconazonium sulfate (Cresemba).In some embodiments, the CYP3A4 substrate drugs can include lomitapidemesylate (Juxtapid). In some embodiments, the CYP3A4 substrate drugs caninclude iloperidone (Fanapt). In some embodiments, the CYP3A4 substratedrugs can include palbociclib (Ibrance). In some embodiments, the CYP3A4substrate drugs can include levomilnacipran hydrochloride (Fetzima). Insome embodiments, the CYP3A4 substrate drugs can include pimozide(Orap). In some embodiments, the CYP3A4 substrate drugs can includepomalidomide (Pomalyst). In some embodiments, the CYP3A4 substrate drugscan include abemaciclib (Verzenio). In some embodiments, the CYP3A4substrate drugs can include ivacaftor (Kalydeco). In some embodiments,the CYP3A4 substrate drugs can include ruxolitinib phosphate (Jakafi).In some embodiments, the CYP3A4 substrate drugs can includebrexpiprazole (Rexulti). In some embodiments, the CYP3A4 substrate drugscan include ivacaftor/tezacaftor (Symdeko). In some embodiments, theCYP3A4 substrate drugs can include regorafenib (Stivarga). In someembodiments, the CYP3A4 substrate drugs can include daclatasvir(Daklinza). In some embodiments, the CYP3A4 substrate drugs can includecrizotinib (Xalkori). In some embodiments, the CYP3A4 substrate drugscan include naloxegol oxalate (Movantik). In some embodiments, theCYP3A4 substrate drugs can include dabrafenib (Tafinlar). In someembodiments, the CYP3A4 substrate drugs can include elbasvir andgrazoprevir (Zepatier). In some embodiments, the CYP3A4 substrate drugscan include olaparib (Lynparza). In some embodiments, the CYP3A4substrate drugs can include apalutamide (Erleada). In some embodiments,the CYP3A4 substrate drugs can include brigatinib (Alunbrig). In someembodiments, the CYP3A4 substrate drugs can include cannabidiol(Epidiolex). In some embodiments, the CYP3A4 substrate drugs can includecopanlisib (Aliqopa). In some embodiments, the CYP3A4 substrate drugscan include duvelisib (Copiktra). In some embodiments, the CYP3A4substrate drugs can include encorafenib (Braftovi). In some embodiments,the CYP3A4 substrate drugs can include flibanserin (Addyi). In someembodiments, the CYP3A4 substrate drugs can include ivabradine(Corlanor). In some embodiments, the CYP3A4 substrate drugs can includeivosidenib (Tibsovo). In some embodiments, the CYP3A4 substrate drugscan include panobinostat (Farydak). In some embodiments, the CYP3A4substrate drugs can include sonidegib (Odomzo). In some embodiments, theCYP3A4 substrate drugs can include vemurafenib (Zelboraf). Othernon-limiting examples of CYP3A4 substrate drugs include HIV proteaseinhibitors, such as amprenavir (Agenerase), atazanavir (Reyataz),darunavir (Prezista), fosamprenavir (Lexiva, Telzir), indinavir(Crixivan), lopinavir (Kaletra), nelfinavir (Viracept), ritonavir(Norvir), saquinavir (Invirase, Forovase), and tipranavir (Aptivus),benzodiazepines, such as alprazolam (Xanax), clonazepam (Klonopin), anddiazepam (Valium), calcium channel blockers such as amlodipine(Norvasc), aranidipine (Sapresta), azelnidipine (Calblock), barnidipine(HypoCa), benidipine (Coniel), cilnidipine (Atelec, Cinalong, Siscard),clevidipine (Cleviprex), isradipine (DynaCirc, Prescal), efonidipine(Landel), felodipine (Plendil), lacidipine (Motens, Lacipil),lercanidipine (Zanidip), manidipine (Calslot, Madipine), nicardipine(Cardene, Carden SR), nifedipine (Procardia, Adalat), nilvadipine(Nivadil), nimodipine (Nimotop), nisoldipine (Baymycard, Sular, Syscor),nitrendipine (Cardif, Nitrepin, Baylotensin), and pranidipine (Acalas),hydroxymethylglutaryl coenzyme A-reductase inhibitors, such asatorvastatin (Lipitor, Ator), lovastatin (Mevacor, Altocor, Altoprev),mevastatin (Compactin) and simvastatin (Zocor, Lipex), antineoplasticdrugs, such as sorafenib (Nexavar) and sunitinib (Sutent), nonsedatingantihistamines, such as fexofenadine (Allegra), loratadine (Claritin),desloratadine (Clarinex), cetirizine (Zyrtec), levocetirizine (Xyza) andimmunosuppressants, such as cyclosporin.

In some embodiments, the CYP3A4 substrate drug used in the methodsdisclosed herein can be any drug metabolized by CYP3A4, in particulardrugs metabolized by CYP3A4 and which are contraindicated for use withstrong CYP3A4 inhibitors or include dose adjustment recommendations forconcomitant administration with CYP3A4 inhibitors. In some embodiments,the methods described herein can be applied to any therapeutic regimenin which one or more CYP3A4 substrate drug(s) described herein are usedto treat a patient previously on posaconazole, including therapeuticregimens that entail treating a patient with a CYP3A4 substrate drug incombination with other drugs.

In some embodiments, the CYP3A4 substrate drug can be indicated for thetreatment of disease or condition selected from the group consisting ofschizophrenia in adults and adolescents (13 to 17 years), depressiveepisodes associated with Bipolar I Disorder (bipolar depression) inadults and pediatrics (10 to 17 years) as monotherapy or adjunctivetherapy with lithium or valproate, moderate bipolar depression, severebipolar depression, and severe bipolar depression with acute suicidalidealation and behavior (ASIB), chronic angina, cystic fibrosis inpatients 6 years and older who are homozygous for the F508del mutationin the CFTR gene, chronic lymphocytic leukemia in patients with 17pdeletion, who have received at least one prior therapy, unresectable ormetastatic liposarcoma or leiomyosarcoma in patients who received aprior anthracycline-containing regimen, advanced or metastatic breastcancer in postmenopausal women with hormone receptor (HR)-positive,human epidermal growth factor receptor 2 (HER2)-negative advanced ormetastatic breast cancer, negative advanced or metastatic breast cancerin combination with an aromatase inhibitor for postmenopausal women,Duchenne muscular dystrophy (DMD), secondary hyperparathyroidism (HPT)in patients with chronic kidney disease (CKD) on dialysis, hypercalcemiain patients with parathyroid carcinoma or in patients with primary HPTfor who parathyroidectomy would be indicated on the basis of serumcalcium levels, but who are unable to undergo parathyroidectomy,hallucinations and delusions associated with Parkinson's diseasepsychosis, schizophrenia, acute manic or mixed episodes associated withbipolar I disorder, chronic hepatitis C (CHC) infection as a componentof a combination antiviral treatment regimen with peginterferon alfa andribavirin in HCV genotype 1 infected subjects with compensated liverdisease, advanced hormone receptor-positive, HER2-negative breast cancer(advanced HR+BC) in postmenopausal women in combination with exemestaneafter failure of treatment with letrozole or anastrozole, progressiveneuroendocrine tumors of pancreatic origin (PNET), progressive,well-differentiated, non-functional neuroendocrine tumors (NET) ofgastrointestinal (GI) or lung origin that are unresectable, locallyadvanced or metastatic, advanced renal cell carcinoma (RCC), e.g., afterfailure of treatment with sunitinib or sorafenib, renal angiomyolipomaand tuberous sclerosis complex (TSC), not requiring immediate surgery,TSC in patients who have subependymal giant cell astrocytoma (SEGA) thatrequire therapeutic intervention but are not candidates for surgicalresection, type 2 diabetes mellitus in adults as an adjunct to diet andexercise to improve glycemic control, major depressive disorder (MDD),thrombotic cardiovascular events (e.g., cardiovascular death, myocardialinfarction, or stroke) in patients with acute coronary syndrome (ACS),stroke and systemic embolism in patients with nonvalvular atrialfibrillation, deep vein thrombosis (DVT), which may lead to pulmonaryembolism (PE) in patients who have undergone hip or knee replacementsurgery, DVT, PE, recurrent DVT and PE following initial therapy,moderate to severe active rheumatoid arthritis in patients who have hadinadequate response or tolerance to methotrexate, acute migraine with orwithout aura, chronic phase and accelerated phase Philadelphiachromosome positive chronic myeloid leukemia (Ph+ CML) in newlydiagnosed patients or in patients resistant to or intolerant to priortherapy that included imatinib, atrial fibrillation (AF) in patientswith a history of paroxysmal or persistent AF or atrial flutter (AFK),who are in sinus rhythm or will be cardioverted, asthma in patients aged4 years and older, airflow obstruction and reducing exacerbations inpatients with chronic obstructive pulmonary disease, erectiledysfunction (ED), benign prostatic hyperplasia (BPH), pulmonary arterialhypertension (PAH) (WHO Group 1) to improve exercise ability, goutflares, Familial Mediterranean fever, antiretroviral therapy, anxietydisorders, panic disorders, seizures, insomnia, hypertension,cardiovascular disease, hyperlipidemia, cancer, such as primary kidneycancer, advanced primary liver cancer, radioactive iodine resistantadvanced thyroid carcinoma, renal cell carcinoma, imatinib-resistantgastrointestinal stromal tumor, mantle cell lymphoma in patients whohave received at least one prior therapy, chronic lymphocyticleukemia/small lymphocytic lymphoma, chronic lymphocytic leukemia/smalllymphocytic lymphoma with 17p deletion, Waldenström's macroglobulinemia,marginal zone lymphoma who require systemic therapy and have received atleast one prior anti-CD20-based therapy, unresectable or metastaticmelanoma with a BRAF V600E or V600K mutation, allergies,transplantation, hormone-refractory metastatic prostate cancerpreviously treated with a docetaxel-containing treatment regimen,hormone-refractory metastatic prostate cancer previously treated with adocetaxel-containing treatment regimen, treatment of clinicallysignificant hypervolemic and euvolemic hyponatremia, including patientswith heart failure and Syndrome of Inappropriate Antidiuretic Hormone(SIADH), prevention of acute and delayed nausea and vomiting associatedwith initial and repeat courses of highly emetogenic cancer chemotherapy(HEC) including high-dose cisplatin, prevention of delayed nausea andvomiting associated with initial and repeat courses of moderatelyemetogenic cancer chemotherapy (MEC), over-active bladder with symptomsof urge urinary incontinence, urgency, and urinary frequency, metastaticnon-small cell lung cancer (NSCLC) whose tumors have epidermal growthfactor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitutionmutations as detected by an FDA-approved test receiving first-line,maintenance, or second or greater line treatment after progression,locally advanced, unresectable or metastatic pancreatic cancer, incombination with gemcitabine, HER2-positive, metastatic breast cancerwho previously received trastuzumab and a taxane, separately or incombination in patients who have either: received prior therapy formetastatic disease or developed disease recurrence during or within sixmonths of completing adjuvant therapy, chronic, accelerated, or blastphase Ph+ chronic myelogenous leukemia (CML) in adults with resistanceor intolerance to prior therapy, gastrointestinal stromal tumor (GIST)after disease progression on or intolerance to imatinib mesylate,advanced renal cell carcinoma (RCC), progressive, well-differentiatedpancreatic neuroendocrine tumors (pNET) in patients with unresectablelocally advanced or metastatic disease, CCR5-tropic HIV-1 infection inpatients 2 years of age and older weighing at least 10 kg in combinationwith other antiretroviral agents, advanced renal cell carcinoma,advanced soft tissue sarcoma who have received prior chemotherapy, manicand mixed episodes associated with Bipolar I, Major Depressive Disorder,irritability associated with Autistic Disorder, Tourette's disorder,agitation associated with schizophrenia or bipolar mania, advanced renalcell carcinoma after failure of one prior systemic therapy, to improveglycemic control in adults with type 2 diabetes mellitus (T2DM) who haveinadequate control with dapagliflozin or who are already treated withdapagliflozin and saxagliptin, progressive, metastatic medullary thyroidcancer (MTC), advanced renal cell carcinoma (RCC) who have receivedprior anti-angiogenic therapy, chronic phase, accelerated phase, orblast phase chronic myeloid leukemia (CML) or Ph+ ALL in adults for whomno other tyrosine kinase inhibitor (TKI) therapy is indicated,T315I-positive CML (chronic phase, accelerated phase, or blast phase) orT315I-positive Philadelphia chromosome in adults, positive acutelymphoblastic leukemia (Ph+ ALL), invasive aspergillosis, invasivemucormycosis, to reduce low-density lipoprotein cholesterol (LDL-C),total cholesterol (TC), apolipoprotein B (apo B), and non-high densitylipoprotein cholesterol (non-HDL-C) in patients with homozygous familialhypercholesterolemia (HoFH), schizophrenia in adults, hormone receptor(HR)-positive, human epidermal growth factor receptor 2 (HER2)-negativeadvanced or metastatic breast cancer in combination with an aromataseinhibitor as initial endocrine based therapy in postmenopausal women, orfulvestrant in women with disease progression following endocrinetherapy, Major Depressive Disorder (MDD), suppression of motor andphonic tics in patients with Tourette's Disorder who have failed torespond satisfactorily to standard treatment, and treatment of multiplemyeloma in patients who have received at least two prior therapiesincluding lenalidomide and a proteasome inhibitor and have demonstrateddisease progression on or within 60 days of completion of the lasttherapyallergies, transplantation, hormone-refractory metastaticprostate cancer previously treated with a docetaxel-containing treatmentregimen, hormone-refractory metastatic prostate cancer previouslytreated with a docetaxel-containing treatment regimen, treatment ofclinically significant hypervolemic and euvolemic hyponatremia,including patients with heart failure and Syndrome of InappropriateAntidiuretic Hormone (SIADH), prevention of acute and delayed nausea andvomiting associated with initial and repeat courses of highly emetogeniccancer chemotherapy (HEC) including high-dose cisplatin, prevention ofdelayed nausea and vomiting associated with initial and repeat coursesof moderately emetogenic cancer chemotherapy (MEC), over-active bladderwith symptoms of urge urinary incontinence, urgency, and urinaryfrequency, metastatic non-small cell lung cancer (NSCLC) whose tumorshave epidermal growth factor receptor (EGFR) exon 19 deletions or exon21 (L858R) substitution mutations as detected by an FDA-approved testreceiving first-line, maintenance, or second or greater line treatmentafter progression, locally advanced, unresectable or metastaticpancreatic cancer, in combination with gemcitabine, HER2-positive,metastatic breast cancer who previously received trastuzumab and ataxane, separately or in combination in patients who have either:received prior therapy for metastatic disease or developed diseaserecurrence during or within six months of completing adjuvant therapy,chronic, accelerated, or blast phase Ph+ chronic myelogenous leukemia(CML) in adults with resistance or intolerance to prior therapy,gastrointestinal stromal tumor (GIST) after disease progression on orintolerance to imatinib mesylate, advanced renal cell carcinoma (RCC),progressive, well-differentiated pancreatic neuroendocrine tumors (pNET)in patients with unresectable locally advanced or metastatic disease,CCR5-tropic HIV-1 infection in patients 2 years of age and olderweighing at least 10 kg in combination with other antiretroviral agents,advanced renal cell carcinoma, advanced soft tissue sarcoma who havereceived prior chemotherapy, manic and mixed episodes associated withBipolar I, Major Depressive Disorder, irritability associated withAutistic Disorder, Tourette's disorder, agitation associated withschizophrenia or bipolar mania, advanced renal cell carcinoma afterfailure of one prior systemic therapy, to improve glycemic control inadults with type 2 diabetes mellitus (T2DM) who have inadequate controlwith dapagliflozin or who are already treated with dapagliflozin andsaxagliptin, progressive, metastatic medullary thyroid cancer (MTC),advanced renal cell carcinoma (RCC) who have received prioranti-angiogenic therapy, chronic phase, accelerated phase, or blastphase chronic myeloid leukemia (CML) or Ph+ ALL in adults for whom noother tyrosine kinase inhibitor (TKI) therapy is indicated,T315I-positive CML (chronic phase, accelerated phase, or blast phase) orT315I-positive Philadelphia chromosome in adults, positive acutelymphoblastic leukemia (Ph+ ALL), invasive aspergillosis, invasivemucormycosis, to reduce low-density lipoprotein cholesterol (LDL-C),total cholesterol (TC), apolipoprotein B (apo B), and non-high densitylipoprotein cholesterol (non-HDL-C) in patients with homozygous familialhypercholesterolemia (HoFH), schizophrenia in adults, hormone receptor(HR)-positive, human epidermal growth factor receptor 2 (HER2)-negativeadvanced or metastatic breast cancer in combination with an aromataseinhibitor as initial endocrine based therapy in postmenopausal women, orfulvestrant in women with disease progression following endocrinetherapy, Major Depressive Disorder (MDD), suppression of motor andphonic tics in patients with Tourette's Disorder who have failed torespond satisfactorily to standard treatment, treatment of multiplemyeloma in patients who have received at least two prior therapiesincluding lenalidomide and a proteasome inhibitor and have demonstrateddisease progression on or within 60 days of completion of the lasttherapy, non-small cell lung cancer (NSCLC) whose disease has notprogressed after four cycles of platinum-based first-line chemotherapy,locally advanced or metastatic NSCLC after failure of at least one priorchemotherapy regimen, locally advanced, unresectable or metastaticpancreatic cancer, overactive bladder with symptoms of urge urinaryincontinence, urgency, and urinary frequency, advanced renal cellcarcinoma (RCC) after failure of treatment with sunitinib or sorafenib,subependymal giant cell astrocytoma (SEGA) associated with tuberoussclerosis (TS) who require therapeutic intervention but are notcandidates for curative surgical resection, renal angiomyolipoma,tuberous sclerosis complex, hormone receptor (HR)-positive, humanepidermal growth factor receptor 2 (HER2)-negative advanced ormetastatic breast cancer with disease progression following endocrinetherapy in women in combination with fulvestrant, as monotherapy for thetreatment of adult patients with HRpositive, HER2-negative advanced ormetastatic breast cancer with disease progression following endocrinetherapy and prior chemotherapy in the metastatic setting, cysticfibrosis (CF) in patients age 2 years and older who have one mutation inthe CFTR gene that is responsive to ivacaftor based on clinical and/orin vitro assay data, deleterious or suspected deleterious germlineBRCA-mutated advanced ovarian cancer in adult patients who have beentreated with three or more prior lines of chemotherapy, intermediate orhigh-risk myelofibrosis, including primary myelofibrosis,post-polycythemia vera myelofibrosis and post-essential thrombocythemiamyelofibrosis, polycythemia vera patients who have had an inadequateresponse to or are intolerant of hydroxyurea, as an adjunctive therapyto antidepressants for the treatment of major depressive disorder (MDD),schizophrenia, cystic fibrosis (CF) patients aged 12 years and older whoare homozygous for the F508del mutation or who have at least onemutation in the cystic fibrosis transmembrane conductance regulator(CFTR) gene that is responsive to tezacaftor/ivacaftor based on in vitrodata and/or clinical evidence, metastatic colorectal cancer (CRC)patients who have been previously treated with fluoropyrimidine-,oxaliplatin- and irinotecan-based chemotherapy, an antiVEGF therapy,and, if RAS wild-type, an anti-EGFR therapy, locally advanced,unresectable or metastatic gastrointestinal stromal tumor (GIST)patients who have been previously treated with imatinib mesylate andsunitinib malate, hepatocellular carcinoma (HCC) who have beenpreviously treated with sorafenib, chronic HCV genotype 1 or 3 infectionwith sofosbuvir and with or without ribavirin, metastatic non-small celllung cancer (NSCLC) patients whose tumors are anaplastic lymphoma kinase(ALK) or ROS1-positive as detected by an FDA-approved test, opioidinduced constipation (OIC) in adult patients with chronic non-cancerpain, including patients with chronic pain related to prior cancer orits treatment who do not require frequent (e.g., weekly) opioid dosageescalation, unresectable or metastatic melanoma in patients with BRAFV600E mutation as detected by an FDA-approved test, in combination withtrametinib, unresectable or metastatic melanoma in patients with BRAFV600E or V600K mutations as detected by an FDA-approved test, adjuvanttreatment of patients with melanoma in patients BRAF V600E or V600Kmutations, as detected by an FDA-approved test, and involvement of lymphnode(s), following complete resection, metastatic non-small cell lungcancer (NSCLC) in patients with BRAF V600E mutation as detected by anFDA-approved test, locally advanced or metastatic anaplastic thyroidcancer (ATC) in patients with BRAF V600E mutation and with nosatisfactory locoregional treatment options, with or without ribavirinfor treatment of chronic HCV genotypes 1 or 4 infection in adults, thetreatment of patients with non-metastatic castration-resistant prostatecancer, the treatment of patients with anaplastic lymphoma kinase(ALK)-positive metastatic non-small cell lung cancer (NSCLC) who haveprogressed on or are intolerant to crizotinib, the treatment of seizuresassociated with Lennox-Gastaut syndrome or Dravet syndrome in patients 2years of age and older, the treatment of adult patients with relapsedfollicular lymphoma (FL) who have received at least two prior systemictherapies, the treatment of adult patients with relapsed or refractorychronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL)after at least two prior therapies, the treatment of adult patients withrelapsed or refractory follicular lymphoma (FL) after at least two priorsystemic therapies, in combination with binimetinib, for the treatmentof patients with unresectable or metastatic melanoma with a BRAF V600Eor V600K mutation, as detected by an FDA-approved test, the treatment ofpremenopausal women with acquired, generalized hypoactive sexual desiredisorder (HSDD) as characterized by low sexual desire that causes markeddistress or interpersonal difficulty and is not due to a co-existingmedical or psychiatric condition, problems within the relationship, orthe effects of a medication or other drug substance, to reduce the riskof hospitalization for worsening heart failure in patients with stable,symptomatic chronic heart failure with left ventricular ejectionfraction ≤35%, who are in sinus rhythm with resting heart rate ≥70 beatsper minute and either are on maximally tolerated doses of beta-blockersor have a contraindication to beta-blocker use, the treatment of adultpatients with relapsed or refractory acute myeloid leukemia (AML) with asusceptible IDH1 mutation as detected by an FDA-approved test, thetreatment of patients with multiple myeloma who have received at least 2prior regimens, including bortezomib and an immunomodulatory agent, thetreatment of adult patients with locally advanced basal cell carcinoma(BCC) that has recurred following surgery or radiation therapy, or thosewho are not candidates for surgery or radiation therapy, the treatmentof patients with unresectable or metastatic melanoma with BRAF V600Emutation as detected by an FDA-approved test, and the treatment ofpatients with Erdheim-Chester Disease with BRAF V600 mutation.

In some embodiments, the CYP3A4 substrate drug can be indicated for thetreatment of schizophrenia in adults and adolescents (13 to 17 years),depressive episodes associated with Bipolar I Disorder (bipolardepression) in adults and pediatrics (10-17 years) as monotherapy or asadjunctive therapy with lithium or valproate, moderate bipolardepression, severe bipolar depression, and severe bipolar depressionwith acute suicidal idealation and behavior (ASIB).

In one embodiment, the CYP3A4 substrate drug can be indicated for thetreatment of chronic angina.

In one embodiment, the CYP3A4 substrate drug can be indicated for thetreatment of cystic fibrosis, e.g., in patients 6 years and older whoare homozygous for the F508del mutation in the CFTR gene.

In one embodiment, the CYP3A4 substrate drug can be indicated for thetreatment of chronic lymphocytic leukemia, e.g., in patients with 17pdeletion, who have received at least one prior therapy.

In one embodiment, the CYP3A4 substrate drug can be indicated for thetreatment of unresectable or metastatic liposarcoma or leiomyosarcoma,e.g., in patients who received a prior anthracycline-containing regimen.

In one embodiment, the CYP3A4 substrate drug can be indicated for thetreatment of advanced or metastatic breast cancer, e.g., inpostmenopausal women with hormone receptor (HR)-positive, humanepidermal growth factor receptor 2 (HER2)-negative advanced ormetastatic breast cancer. In a further embodiment, the CYP3A4 substratedrug can be indicated for a treatment of negative advanced or metastaticbreast cancer in postmenopausal women e.g., in combination with anaromatase inhibitor as initial endocrine-based therapy.

In one embodiment, the CYP3A4 substrate drug can be indicated for thetreatment of Duchenne muscular dystrophy (DMD).

In one embodiment, the CYP3A4 substrate drug can be indicated for thetreatment of secondary hyperparathyroidism (HPT), e.g., in patients withchronic kidney disease (CKD) on dialysis. In one embodiment, the CYP3A4substrate drug can be indicated for the treatment of hypercalcemia,e.g., in patients with parathyroid carcinoma. In one embodiment, theCYP3A4 substrate drug can be indicated for the treatment ofhypercalcemia, e.g., in patients with primary HPT for whoparathyroidectomy would be indicated on the basis of serum calciumlevels, but who are unable to undergo parathyroidectomy.

In one embodiment, the CYP3A4 substrate drug can be indicated for thetreatment of hallucinations and delusions associated with Parkinson'sdisease psychosis.

In one embodiment, the CYP3A4 substrate drug can be indicated for thetreatment of schizophrenia.

In one embodiment, the CYP3A4 substrate drug can be indicated for theacute treatment of manic or mixed episodes associated with bipolar Idisorder.

In one embodiment, the CYP3A4 substrate drug can be indicated for thetreatment of chronic hepatitis C (CHC) infection, e. g., as a componentof a combination antiviral treatment regimen with peginterferon alfa andribavirin in HCV genotype 1 infected subjects with compensated liverdisease.

In one embodiment, the CYP3A4 substrate drug can be indicated for thetreatment of postmenopausal women with advanced hormonereceptor-positive, HER2-negative breast cancer (advanced HR+BC), e.g.,in combination with exemestane after failure of treatment with letrozoleor anastrozole. In one embodiment, the CYP3A4 substrate drug can beindicated for the treatment of patients with progressive neuroendocrinetumors of pancreatic origin (PNET). In one embodiment, the CYP3A4substrate drug can be indicated for the treatment of patients withprogressive, well-differentiated, non-functional neuroendocrine tumors(NET) of gastrointestinal (GI) or lung origin that are unresectable,locally advanced or metastatic. In one embodiment, the CYP3A4 substratedrug can be indicated for the treatment of patients with advanced renalcell carcinoma (RCC), e.g., after failure of treatment with sunitinib orsorafenib. In one embodiment, the CYP3A4 substrate drug can be indicatedfor the treatment of patients with renal angiomyolipoma and tuberoussclerosis complex (TSC), not requiring immediate surgery. In oneembodiment, the CYP3A4 substrate drug can be indicated for the treatmentof patients with TSC who have subependymal giant cell astrocytoma (SEGA)that require therapeutic intervention but are not candidates forsurgical resection.

In one embodiment, the CYP3A4 substrate drug can be indicated for thetreatment of type 2 diabetes mellitus, e.g., as an adjunct to diet andexercise to improve glycemic control in adults.

In one embodiment, the CYP3A4 substrate drug can be indicated to reducethe rate of thrombotic cardiovascular events (e.g., cardiovasculardeath, myocardial infarction, or stroke) in patients with acute coronarysyndrome (ACS).

In one embodiment, the CYP3A4 substrate drug can be indicated for thetreatment of major depressive disorder (MDD).

In one embodiment, the CYP3A4 substrate drug can be indicated to reducethe risk of stroke and systemic embolism in patients with nonvalvularatrial fibrillation. In one embodiment, the CYP3A4 substrate drug can beindicated for the prophylaxis of deep vein thrombosis (DVT), which maylead to pulmonary embolism (PE), e.g., in patients who have undergonehip or knee replacement surgery. In one embodiment, the CYP3A4 substratedrug can be indicated for the treatment of DVT or PE. In one embodiment,the CYP3A4 substrate drug can be indicated to reduce the risk ofrecurrent DVT and PE following initial therapy.

In one embodiment, the CYP3A4 substrate drug can be indicated for thetreatment of moderate to severe active rheumatoid arthritis, e.g., inpatients who have had inadequate response or tolerance to methotrexate.

In one embodiment, the CYP3A4 substrate drug can be indicated for theacute treatment of migraine with or without aura.

In one embodiment, the CYP3A4 substrate drug can be indicated for thetreatment of chronic phase and accelerated phase Philadelphia chromosomepositive chronic myeloid leukemia (Ph+ CML), e.g., in newly diagnosedpatients or in patients resistant to or intolerant to prior therapy thatincluded imatinib.

In one embodiment, the CYP3A4 substrate drug can be indicated to reducethe risk of hospitalization for atrial fibrillation (AF), e.g., inpatients with a history of paroxysmal or persistent AF or atrial flutter(AFK), who are in sinus rhythm or will be cardioverted.

In one embodiment, the CYP3A4 substrate drug can be indicated formaintenance treatment of asthma, e.g., in patients aged 4 years andolder. In one embodiment, the CYP3A4 substrate drug can be indicated formaintenance treatment of airflow obstruction and reducing exacerbationsin patients with chronic obstructive pulmonary disease.

In one embodiment, the CYP3A4 substrate drug can be indicated for thetreatment of erectile dysfunction (ED). In one embodiment, the CYP3A4substrate drug can be indicated for the treatment of benign prostatichyperplasia (BPH). In one embodiment, the CYP3A4 substrate drug can beindicated for treatment of pulmonary arterial hypertension (PAH) (WHOGroup 1) to improve exercise ability.

In one embodiment, the CYP3A4 substrate drug can be indicated for thetreatment of gout flares. In one embodiment, the CYP3A4 substrate drugcan be indicated for the treatment of Familial Mediterranean fever.

In one embodiment, the CYP3A4 substrate drug can be indicated for mantlecell lymphoma in patients who have received at least one prior therapy.In one embodiment, the CYP3A4 substrate drug can be indicated forchronic lymphocytic leukemia/small lymphocytic lymphoma. In oneembodiment, the CYP3A4 substrate drug can be indicated for chroniclymphocytic leukemia/small lymphocytic lymphoma with 17p deletion.

In one embodiment, the CYP3A4 substrate drug can be indicated forWaldenström's macroglobulinemia.

In one embodiment, the CYP3A4 substrate drug can be indicated formarginal zone lymphoma who require systemic therapy and have received atleast one prior anti-CD20-based therapy.

In one embodiment, the CYP3A4 substrate drug can be indicated forunresectable or metastatic melanoma with a BRAF V600E or V600K mutation.

In one embodiment, the CYP3A4 substrate drug can be indicated for thetreatment of hormone-refractory metastatic prostate cancer previouslytreated with a docetaxel-containing treatment regimen.

In one embodiment, the CYP3A4 substrate drug can be indicated fortreatment of clinically significant hypervolemic and euvolemichyponatremia; including patients with heart failure and Syndrome ofInappropriate Antidiuretic Hormone (SIADH).

In one embodiment, the CYP3A4 substrate drug can be indicated for theprevention of acute and delayed nausea and vomiting associated withinitial and repeat courses of highly emetogenic cancer chemotherapy(HEC) including high-dose cisplatin.

In one embodiment, the CYP3A4 substrate drug can be indicated for theprevention of delayed nausea and vomiting associated with initial andrepeat courses of moderately emetogenic cancer chemotherapy (MEC).

In one embodiment, the CYP3A4 substrate drug can be indicated fortreatment of over-active bladder with symptoms of urge urinaryincontinence, urgency, and urinary frequency.

In one embodiment, the CYP3A4 substrate drug can be indicated for thetreatment of patients with metastatic non-small cell lung cancer (NSCLC)whose tumors have epidermal growth factor receptor (EGFR) exon 19deletions or exon 21 (L858R) substitution mutations as detected by anFDA-approved test receiving first-line, maintenance, or second orgreater line treatment after progression.

In one embodiment, the CYP3A4 substrate drug can be indicated for thefirst-line treatment of patients with locally advanced, unresectable ormetastatic pancreatic cancer, in combination with gemcitabine.

In one embodiment, the CYP3A4 substrate drug can be indicated for thetreatment of patients with HER2-positive, metastatic breast cancer whopreviously received trastuzumab and a taxane, separately or incombination in patients who have either: received prior therapy formetastatic disease or developed disease recurrence during or within sixmonths of completing adjuvant therapy.

In one embodiment, the CYP3A4 substrate drug can be indicated for thetreatment of adult patients with chronic, accelerated, or blast phasePh+ chronic myelogenous leukemia (CML) with resistance or intolerance toprior therapy.

In one embodiment, the CYP3A4 substrate drug can be indicated for thetreatment of gastrointestinal stromal tumor (GIST) after diseaseprogression on or intolerance to imatinib mesylate.

In one embodiment, the CYP3A4 substrate drug can be indicated for thetreatment of advanced renal cell carcinoma (RCC); progressive,well-differentiated pancreatic neuroendocrine tumors (pNET) in patientswith unresectable locally advanced or metastatic disease.

In one embodiment, the CYP3A4 substrate drug can be indicated for thetreatment of only CCR5-tropic HIV-1 infection in patients 2 years of ageand older weighing at least 10 kg in combination with otherantiretroviral agents.

In one embodiment, the CYP3A4 substrate drug can be indicated for thetreatment of patients with advanced renal cell carcinoma.

In one embodiment, the CYP3A4 substrate drug can be indicated for thetreatment of patients with advanced soft tissue sarcoma who havereceived prior chemotherapy.

In one embodiment, the CYP3A4 substrate drug can be indicated for theacute treatment of manic and mixed episodes associated with Bipolar I.

In one embodiment, the CYP3A4 substrate drug can be indicated for theadjunctive treatment of Major Depressive Disorder.

In one embodiment, the CYP3A4 substrate drug can be indicated for thetreatment of irritability associated with Autistic Disorder.

In one embodiment, the CYP3A4 substrate drug can be indicated for thetreatment of Tourette's disorder.

In one embodiment, the CYP3A4 substrate drug can be indicated for thetreatment of agitation associated with schizophrenia or bipolar mania.

In one embodiment, the CYP3A4 substrate drug can be indicated for thetreatment of advanced renal cell carcinoma after failure of one priorsystemic therapy.

In one embodiment, the CYP3A4 substrate drug can be indicated to improveglycemic control in adults with type 2 diabetes mellitus (T2DM) who haveinadequate control with dapagliflozin or who are already treated withdapagliflozin and saxagliptin.

In one embodiment, the CYP3A4 substrate drug can be indicated for thetreatment of patients with progressive, metastatic medullary thyroidcancer (MTC).

In one embodiment, the CYP3A4 substrate drug can be indicated for thetreatment of patients with advanced renal cell carcinoma (RCC) who havereceived prior anti-angiogenic therapy.

In one embodiment, the CYP3A4 substrate drug can be indicated for thetreatment of adult patients with chronic phase, accelerated phase, orblast phase chronic myeloid leukemia (CML) or Ph+ ALL for whom no othertyrosine kinase inhibitor (TKI) therapy is indicated.

In one embodiment, the CYP3A4 substrate drug can be indicated for thetreatment of adult patients with T315I-positive CML (chronic phase,accelerated phase, or blast phase) or T315I-positive Philadelphiachromosome positive acute lymphoblastic leukemia (Ph+ ALL).

In one embodiment, the CYP3A4 substrate drug can be indicated for thetreatment of invasive aspergillosis.

In one embodiment, the CYP3A4 substrate drug can be indicated for thetreatment of invasive mucormycosis; to reduce low-density lipoproteincholesterol (LDL-C), total cholesterol (TC), apolipoprotein B (apo B),and non-high density lipoprotein cholesterol (non-HDL-C) in patientswith homozygous familial hypercholesterolemia (HoFH).

In one embodiment, the CYP3A4 substrate drug can be indicated for thetreatment of schizophrenia in adults.

In one embodiment, the CYP3A4 substrate drug can be indicated for thetreatment of hormone receptor (HR)-positive; human epidermal growthfactor receptor 2 (HER2)-negative advanced or metastatic breast cancerin combination with an aromatase inhibitor as initial endocrine basedtherapy in postmenopausal women, or fulvestrant in women with diseaseprogression following endocrine therapy.

In one embodiment, the CYP3A4 substrate drug can be indicated for thetreatment of Major Depressive Disorder (MDD).

In one embodiment, the CYP3A4 substrate drug can be indicated for thesuppression of motor and phonic tics in patients with Tourette'sDisorder who have failed to respond satisfactorily to standardtreatment.

In one embodiment, the CYP3A4 substrate drug can be indicated for thetreatment of multiple myeloma in patients who have received at least twoprior therapies including lenalidomide and a proteasome inhibitor andhave demonstrated disease progression on or within 60 days of completionof the last therapy.

In one embodiment, the CYP3A4 substrate drug can be indicated for thetreatment of non-small cell lung cancer (NSCLC) whose disease has notprogressed after four cycles of platinum-based first-line chemotherapy.

In one embodiment, the CYP3A4 substrate drug can be indicated for thetreatment of locally advanced or metastatic NSCLC after failure of atleast one prior chemotherapy regimen.

In one embodiment, the CYP3A4 substrate drug can be indicated for thetreatment of locally advanced, unresectable or metastatic pancreaticcancer.

In one embodiment, the CYP3A4 substrate drug can be indicated for thetreatment of overactive bladder with symptoms of urge urinaryincontinence, urgency, and urinary frequency.

In one embodiment, the CYP3A4 substrate can be indicated for thetreatment of advanced renal cell carcinoma (RCC) after failure oftreatment with sunitinib or sorafenib.

In one embodiment, the CYP3A4 substrate drug can be indicated for thetreatment of subependymal giant cell astrocytoma (SEGA) associated withtuberous sclerosis complex (TSC) who require therapeutic interventionbut are not candidates for curative surgical resection.

In one embodiment, the CYP3A4 substrate drug can be indicated for thetreatment of renal angiomyolipoma and tuberous sclerosis complex.

In one embodiment, the CYP3A4 substrate drug can be indicated for thetreatment of hormone receptor (HR)-positive, human epidermal growthfactor receptor 2 (HER2)-negative advanced or metastatic breast cancerwith disease progression following endocrine therapy in women incombination with fulvestrant.

In one embodiment, the CYP3A4 substrate drug can be used as monotherapyfor the treatment of adult patients with HRpositive, HER2-negativeadvanced or metastatic breast cancer with disease progression followingendocrine therapy and prior chemotherapy in the metastatic setting.

In one embodiment, the CYP3A4 substrate drug can be indicated for thetreatment of cystic fibrosis (CF) in patients age 2 years and older whohave one mutation in the CFTR gene that is responsive to ivacaftor basedon clinical and/or in vitro assay data.

In one embodiment, the CYP3A4 substrate drug can be indicated for thetreatment of deleterious or suspected deleterious germline BRCA-mutatedadvanced ovarian cancer in adult patients who have been treated withthree or more prior lines of chemotherapy.

In one embodiment, the CYP3A4 substrate drug can be indicated for thetreatment of intermediate or high-risk myelofibrosis, including primarymyelofibrosis, post-polycythemia vera myelofibrosis and post-essentialthrombocythemia myelofibrosis.

In one embodiment, the CYP3A4 substrate drug can be indicated for thetreatment of polycythemia vera patients who have had an inadequateresponse to or are intolerant of hydroxyurea.

In one embodiment, the CYP3A4 substrate drug can be indicated as anadjunctive therapy to antidepressants for the treatment of majordepressive disorder (MDD).

In one embodiment, the CYP3A4 substrate drug can be indicated for thetreatment of schizophrenia.

In one embodiment, the CYP3A4 substrate drug can be indicated for thetreatment of cystic fibrosis (CF) patients aged 12 years and older whoare homozygous for the F508del mutation or who have at least onemutation in the cystic fibrosis transmembrane conductance regulator(CFTR) gene that is responsive to tezacaftor/ivacaftor based on in vitrodata and/or clinical evidence.

In one embodiment, the CYP3A4 substrate drug can be indicated for thetreatment of metastatic colorectal cancer (CRC) patients who have beenpreviously treated with fluoropyrimidine-, oxaliplatin- andirinotecan-based chemotherapy, an antiVEGF therapy, and, if RASwild-type, an anti-EGFR therapy.

In one embodiment, the CYP3A4 substrate drug can be indicated for thetreatment of locally advanced, unresectable or metastaticgastrointestinal stromal tumor (GIST) patients who have been previouslytreated with imatinib mesylate and sunitinib malate.

In one embodiment, the CYP3A4 substrate drug can be indicated for thetreatment of hepatocellular carcinoma (HCC) in patients who have beenpreviously treated with sorafenib.

In one embodiment, the CYP3A4 substrate drug can be indicated for theuse with sofosbuvir, with or without ribavirin, for the treatment ofchronic HCV genotype 1 or 3 infection.

In one embodiment, the CYP3A4 substrate drug can be indicated for thetreatment of metastatic non-small cell lung cancer (NSCLC) patientswhose tumors are anaplastic lymphoma kinase (ALK) or ROS1-positive asdetected by an FDA-approved test.

In one embodiment, the CYP3A4 substrate drug can be indicated for thetreatment of opioid induced constipation (OIC) in adult patients withchronic non-cancer pain, including patients with chronic pain related toprior cancer or its treatment who do not require frequent (e.g., weekly)opioid dosage escalation.

In one embodiment, the CYP3A4 substrate drug can be indicated for thetreatment of unresectable or metastatic melanoma with BRAF V600Emutation as detected by an FDA-approved test.

In one embodiment, the CYP3A4 substrate drug can be indicated incombination with trametinib, for the treatment of patients withunresectable or metastatic melanoma with BRAF V600E or V600K mutationsas detected by an FDA-approved test.

In one embodiment, the CYP3A4 substrate drug can be indicated incombination with trametinib, for the treatment of patients with melanomawith BRAF V600E or V600K mutations, as detected by an FDA-approved test,and involvement of lymph node(s), following complete resection.

In one embodiment, the CYP3A4 substrate drug can be indicated incombination with trametinib, for the treatment of metastatic non-smallcell lung cancer (NSCLC) with BRAF V600E mutation as detected by anFDA-approved test.

In one embodiment, the CYP3A4 substrate drug can be indicated incombination with trametinib, for the treatment of locally advanced ormetastatic anaplastic thyroid cancer (ATC) with BRAF V600E mutation andwith no satisfactory locoregional treatment options.

In one embodiment, the CYP3A4 substrate drug can be indicated with orwithout ribavirin for treatment of chronic HCV genotypes 1 or 4infection in adults.

Other non-limiting examples of conditions or diseases for which CYP3A4substrate drugs are prescribed include antiretroviral therapy, e.g., forthe treatment of HIV/AIDS, anxiety disorders, panic disorders, seizures,insomnia, hypertension, cardiovascular disease (e.g., myocardialinfarction, stroke, and angina), hyperlipidemia, cancer, such as primarykidney cancer, advanced primary liver cancer, radioactive iodineresistant advanced thyroid carcinoma, renal cell carcinoma,imatinib-resistant gastrointestinal stromal tumor, allergies, andtransplantation.

As discussed above, after stopping treatment with a strong CYP3A4inhibitor (including but not limited to posaconazole), posaconazoleaccumulates in the body of patients, and reduces or prevents metabolismof CYP3A4 substrate drugs. Thus, patients previously on posaconazolethat are concomitantly treated with CYP3A4 substrate drugs may haveplasma levels of the CYP3A4 substrate drug that exceed the plasma levelsof an otherwise identical patient that was not previously treated withposaconazole. Described herein, in various embodiments, are treatmentregimens for CYP3A4 substrate drugs which are applicable to patients whopreviously received multiple doses of a strong CYP3A4 inhibitor (e.g.,posaconazole) for a period of about 2-21 days after stopping treatmentwith the strong CYP3A4 inhibitor. In some embodiments, the treatmentregimen provides for treating or prescribing a dose which is less thanabout 50% of the reference dose of the CYP3A4 substrate drug for aperiod of about 2-21 days after stopping posaconazole treatment. As usedherein, a dose that is less than 50% of the reference dose of the CYP3A4inhibitor can include any amount from 0% (i.e., no dose) to about 50% ofthe CYP3A4 inhibitor for the period of 2-21 days. Therefore, thetreatment regimen disclosed herein can include, in some embodiments,delaying a first dose of a CYP3A4 substrate drug for about 2-21 daysafter stopping posaconazole treatment, or alternatively, treating with areduced dose of the CYP3A4 substrate drug for about 2-21 days afterstopping posaconazole treatment. The methods described herein can beapplied to any patient that was previously on posaconazole and having anindication amenable to treatment with a CYP3A4 substrate drug, includingnormal patients (non-obese and normal metabolizers), obese patients, andpoor or intermediate metabolizers, or combinations thereof.

In some embodiments, between about 2 and about 42 days, e.g., about 2,about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10,about 11, about 12 days, about 13, about 14, about 15, about 16, about17, about 18, about 19, about 20, about 21 days, about 22 days, about23, about 24, about 25, about 26, about 27, about 28, about 29, about30, about 31 days, about 32 days, about 33, about 34, about 35, about36, about 37, about 38, about 39, about 40, about 41 days, or about 42days inclusive of all ranges and subranges therebetween, should elapsebetween discontinuation of posaconazole (i.e., the last dose in aposaconazole regimen) and initiation of treatment with a CYP3A4substrate drug (i.e., the first dose in a CYP3A4 regimen of any of theCYP3A4 substrate drugs described herein). In some embodiments, thepatient is a “normal” patient (i.e., a patient with “normal” CYP3A4enzyme function, often termed an “extensive metabolizer” in the art; andhaving a normal weight—e.g., a BMI in the range of about 18.5-24.9), andin other embodiments the patient has one of the physiologicalcharacteristics described herein, e.g., is considered obese and/or has alevel of CYP3A4 enzyme activity termed in the art as poor orintermediate.

This “delay” or waiting period between ceasing or stopping the treatmentof posaconazole and initiating treatment with a CYP3A4 substrate drugcan equivalently be characterized as the time that elapses betweenstopping treatment of posaconazole and treating with the first dose ofCYP3A4 substrate drug. The skilled artisan will recognize thatadditional doses of the CYP3A4 substrate drug are typically administeredor prescribed subsequently, but the “delay” or “washout” period asdescribed herein is the time that elapses between stopping treatment ofposaconazole and the first dose that initiates treatment with a CYP3A4substrate drug.

In alternative embodiments, rather than delaying the treatment of theCYP3A4 substrate drug, after stopping treatment of posaconazole theCYP3A4 substrate drug is treated or prescribed at a dose which is nomore than about 50% of a reference dose (the dose recommended for thepatient on the FDA-approved label for the CYP3A4 substrate drug),including e.g., no more than about 50%, no more than about 49%, no morethan about 48%, no more than about 47%, no more than about 46%, no morethan about 45%, no more than about 44%, no more than about 43%, no morethan about 42%, no more than about 41%, no more than about 40%, no morethan about 39%, no more than about 38%, no more than about 37%, no morethan about 36%, no more than about 35%, no more than about 34%, no morethan about 33%, no more than about 32%, no more than about 31%, no morethan about 30%, no more than about 29%, no more than about 28%, no morethan about 27%, no more than about 26%, no more than about 25%, no morethan about 24%, no more than about 23%, no more than about 22%, no morethan about 21%, no more than about 20%, no more than about 19%, no morethan about 18%, no more than about 17%, no more than about 16%, no morethan about 15%, no more than about 14%, no more than about 13%, no morethan about 12%, no more than about 11%, or no more than about 10% of thereference dose, inclusive of all ranges and subranges therebetween, forat least about 2-42 days after discontinuation of the posaconazoleregimen, e.g., for about 2, about 3, about 4, about 5, about 6, about 7,about 8, about 9, about 10, about 11, about 12 days, about 13, about 14,about 15, about 16, about 17, about 18, about 19, about 20, about 21days, about 22 days, about 23, about 24, about 25, about 26, about 27,about 28, about 29, about 30, about 31 days, about 32 days, about 33,about 34, about 35, about 36, about 37, about 38, about 39, about 40,about 41 days, or about 42 days, inclusive of all ranges and subrangestherebetween.

In other alternative embodiments, depending on the CYP3A4 substratedrug, the patient can be treated with or prescribed a CYP3A4 substratedrug at a dose which is less than 100% of a reference dose (the doserecommended for the patient on the FDA-approved label for the CYP3A4substrate drug), including e.g., about 95%, about 90%, about 85%, about80%, about 75%, about 70%, about 65%, about 60%, about 55%, or about 50%of the reference dose, inclusive of all ranges and subrangestherebetween, for at least about 2-42 days after discontinuation of theposaconazole treatment, e.g., for about 2, about 3, about 4, about 5,about 6, about 7, about 8, about 9, about 10, about 11, about 12 days,about 13, about 14, about 15, about 16, about 17, about 18, about 19,about 20, about 21 days, about 22 days, about 23, about 24, about 25,about 26, about 27, about 28, about 29, about 30, about 31 days, about32 days, about 33, about 34, about 35, about 36, about 37, about 38,about 39, about 40, about 41 days, or about 42 days inclusive of allranges and subranges therebetween.

In addition to providing methods of treating or prescribing treatmentfor “normal” patients (e.g., non-obese and normal CYP3A4 metabolizers),the present disclosure also provides methods for treating, orprescribing treatment for, patients with at least one of thephysiological characteristics described herein, who had been treatedwith multiple doses of posaconazole, with a CYP3A4 substrate drug. Thetreatment with the CYP3A4 substrate drug is initiated or prescribed tobe initiated (or the first dosing begins after stopping treatment withposaconazole) after a delay time as described herein, or is treated orprescribed at a reduced dose (e.g., any amount less than 100% of areference dose, including but not limited to about ⅓, about ½, about ⅔,etc. of a reference dose) for a time period after treatment withposaconazole is stopped as described herein. The physiologicalcharacteristics of such patients include reduced hepatic enzymefunction, specifically reduced CYP3A4 enzyme function (such patients arecharacterized in the art as intermediate or poor CYP3A4 metabolizers),and/or a weight or body fat status variously characterized as describedherein. In some embodiments, the patients can have variouscharacteristics of body fat status. The term “body fat status,” “bodyfat characteristics,” “obese status,” “obese characteristics,” or otherderivations or variations thereof refer to at least sevencharacteristics (BMI, % IBW, waist size, % body fat, % android fat, %gynoid fat, and total body fat) as described herein. In someembodiments, the body fat status may be referred to as obesity, and thepatients may be referred to as obese, or obese patients.

As described herein, the present Applicants have found that certainclasses of patients, i.e., patients having the particular physiologicalcharacteristics described herein such as body fat and weight statusand/or hepatic metabolizing enzyme status, after stopping treatment withposaconazole, may have substantially higher plasma levels ofposaconazole and/or exhibit substantially longer elimination half-lives(t_(1/2)) of posaconazole than previously known or contemplated, e.g.,in the NOXAFIL® label, and therefore require either a delay as describedherein after stopping posaconazole treatment, before treating, orprescribing a first treatment to begin, with a CYP3A4 substrate drug, ora dose adjustment (reduction) of the CYP3A4 substrate drug for a timeperiod after stopping posaconazole treatment, as described herein. Insome embodiments, the duration of the delay period or dose adjustmentperiod, or the degree of dose adjustment is greater than thecorresponding delay or dose reduction period/amount compared to thoseconsidered to be “normal” patients. These classes of patients whichexhibit substantially higher plasma levels of posaconazole, and/orexhibit substantially longer elimination half-lives (t_(1/2)) ofposaconazole compared to the expected level (e.g., as embodied in therecommendations of the NOXAFIL® label), or who require a longer delaytime, dose adjustment time, or dose adjustment level include obesepatients who exhibit one or more of e.g., a BMI of at least about 35, %IBW of at least about 150%, waist size greater than about 42 inches, %body fat greater than about 40%, % android body fat greater than about40%, % gynoid body fat greater than about 40%, total body fat greaterthan about 40 kg, optionally in combination with impaired hepaticfunction, e.g., intermediate or poor CYP3A4 metabolizers. Alternatively,patients who are not obese (e.g., have any of the various measures ofbody fat status described herein which are not considered as indicativeof obesity, such as a BMI less than about 35, % IBW of less than about150%, waist size less than about 42 inches, % body fat less than about40%, % android body fat less than about 40%, % gynoid body fat less thanabout 40%, or total body fat less than about 40 kg) but have impairedhepatic metabolic function, e.g., are considered intermediate or poorCYP3A4 metabolizers, have also been found by the present Applicants tohave substantially higher steady state plasma levels of posaconazole,and/or exhibit a substantially longer elimination half-lives (t_(1/2))of posaconazole compared to those expected in “normal” patients—i.e.,patients who do not exhibit the specific physiological characteristicsdescribed herein—or as embodied in the recommendations of the NOXAFIL®label may also require an extended washout period (as described herein)after stopping administration of posaconazole before beginning treatmentwith a CYP3A4 substrate drug. Alternatively, such patients may requirean extended period (as described herein) after stopping administrationof posaconazole before beginning treatment with a reduced dose (asdescribed herein) relative to the reference dose of the CYP3A4 substratedrug in order to minimize or avoid adverse effects such as QTcprolongation or other side effects of the CYP3A4 substrate drug than hashitherto been recognized in the art. Conventionally, no such distinctionbetween patients having such physiological characteristics has beenrecognized as requiring increased “washout” periods between dosing withposaconazole and a CYP3A4 substrate drug, or as requiring time periodsduring which a patient is treated, or prescribed to be treated, with areduced reference dose of the CYP3A4 substrate drug after stoppingadministration of posaconazole, as the effects of such physiologicalcharacteristics on steady state plasma levels of posaconazole and/orelimination half-life was not previously known.

Each individual may have different activity levels of the CYP450isozymes that metabolize drugs. Categorizations of metabolizers mayinclude, but are not limited to, allelic heterogeneity in the CYP540isozymes gene. For instance, the CYP3A4 gene can have allelicheterogeneity and expression of CYP3A4*22 allele can be used to classifyindividuals as reduced-expressers of CYP3A4 (i.e., individualspossessing one CYP3A4*22 allele), and normal-expressers of CYP3A4 (i.e.,individuals not possessing any CYP3A4*22 allele).

In some embodiments, the class of patients treated by the methods of thepresent disclosure have a body mass index (BMI; expressed in units ofkg/m² unless otherwise specified) of less than about 25, e.g., about24.5, about 24, about 23.5, about 23, about 22.5, about 22, about 21.5,about 21, about 20.5, about 20, about 19.5, about 19, or about 18.5 orless, inclusive of all values and ranges therebetween.

In some embodiments, the class of patients treated by the methods of thepresent disclosure have a body mass index (BMI; expressed in units ofkg/m² unless otherwise specified) of at least about 25, at least about26, at least about 27, at least about 28, at least about 29, at leastabout 30, at least about 31, at least about 32, at least about 33, atleast about 34, at least about 35, at least about 36, at least about 37,at least about 38, at least about 39, at least about 40, at least about41, at least about 42, at least about 43, at least about 44, at leastabout 45, at least about 46, at least about 47, at least about 48, atleast about 49, at least about 50, at least about 51, at least about 52,at least about 53, at least about 54, at least about 55, at least about56, at least about 57, at least about 58, at least about 59, at leastabout 60, at least about 61, at least about 62, at least about 63, atleast about 64, at least about 65, at least about 66, at least about 67,at least about 68, at least about 69, at least about 70, at least about71, at least about 72, at least about 73, at least about 74, at leastabout 75, at least about 76, at least about 77, at least about 78, atleast about 79, at least about 80, at least about 81, at least about 82,at least about 83, at least about 84, at least about 85, at least about86, at least about 87, at least about 88, at least about 89, at leastabout 90, at least about 91, at least about 92, at least about 93, atleast about 94, at least about 95, at least about 96, at least about 97,at least about 98, at least about 99, at least about 100, at least about101, at least about 102, at least about 103, at least about 104, atleast about 105, at least about 106, at least about 107, at least about108, at least about 109, at least about 110, at least about 111, atleast about 112, at least about 113, at least about 114, at least about115, at least about 116, at least about 117, at least about 118, atleast about 119, at least about 120, at least about 121, at least about122, at least about 123, at least about 124, at least about 125, atleast about 126, at least about 127, at least about 128, at least about129, at least about 130, at least about 131, at least about 132, atleast about 133, at least about 134, at least about 135, at least about136, at least about 137, at least about 138, at least about 139, atleast about 140, at least about 141, at least about 142, at least about143, at least about 144, at least about 145, at least about 146, atleast about 147, at least about 148, at least about 149, at least about150, at least about 151, at least about 152, at least about 153, atleast about 154, at least about 155, at least about 156, at least about157, at least about 158, at least about 159, at least about 160, atleast about 161, at least about 162, at least about 163, at least about164, at least about 165, at least about 166, at least about 167, atleast about 168, at least about 169, at least about 170, at least about171, at least about 172, at least about 173, at least about 174, atleast about 175, at least about 176, at least about 177, at least about178, at least about 179, at least about 180, at least about 181, atleast about 182, at least about 183, at least about 184, at least about185, at least about 186, at least about 187, at least about 188, atleast about 189, at least about 190, at least about 191, at least about192, at least about 193, at least about 194, at least about 195, atleast about 195, at least about 196, at least about 197, at least about198, at least about 199, at least about 200, at least about 201, atleast about 202, at least about 203, at least about 204, at least about205, at least about 206, at least about 207, at least about 208, atleast about 209, or at least about 210, inclusive of all ranges andsubranges therebetween, and any BMI described herein. In one embodiment,the patient has a body mass index (BMI) of at least about 35. In anotherembodiment, the patient has a body mass index (BMI) of at least about40. In another embodiment, the patient has a body mass index (BMI) of atleast 50.

In some embodiments, a patient treated according to the methods of thepresent invention has a BMI of at least about 25 to at least about 29.9,at least about 25.5 to at least about 29, at least about 26 to at leastabout 28.5, at least about 26.5 to at least about 28, or at least about27 to at least about 27.5, inclusive of all ranges and subrangestherebetween, and can be termed overweight or pre-obese. In someembodiments, a patient with a BMI of at least about 30 to at least about34.9, at least about 30.5 to at least about 34, at least about 31 to atleast about 33.5, at least about 31.5 to at least about 33, or at leastabout 32 to at least about 32.5, inclusive of all ranges and subrangestherebetween can be considered obese. In some embodiments, a patientwith a BMI of at least about 35 to at least about 39.9, at least about35.5 to at least about 39, at least about 36 to at least about 38.5, atleast about 36.5 to at least about 38, or at least about 37 to at leastabout 37.5, inclusive of all ranges and subranges therebetween, and anyBMI described herein, can be considered obese. In other embodiments, apatient treated by the methods of the present disclosure has a BMI of atleast about 35 or more, 40 or more, 50 or more, 60 or more, 70 or more,80 or more, 90 or more, 100 or more, 110 or more, 120 or more, 130 ormore, 140 or more, 150 or more, 160 or more, 170 or more, 180 or more,190 or more, 200 or more, or 210 or more, inclusive of all ranges andsubranges therebetween.

In some embodiments, the patient treated according to the methods of thepresent disclosure is a child or an adolescent with a BMI of at leastabout the 85^(th) percentile to at least about 95^(th) percentile, atleast about the 86^(th) percentile to at least about 94^(th) percentile,at least about the 87^(th) percentile to at least about 93^(th)percentile, at least about the 88^(th) percentile to at least about92^(th) percentile, at least about the 89^(th) percentile to at leastabout 90^(th) percentile, inclusive of all ranges and subrangestherebetween, can be considered overweight or pre-obese. In someembodiments, the patient is a patient with a BMI of at least about the95^(th) percentile, at least about 96^(th) percentile, at least aboutthe 97^(th) percentile, at least about 98^(th) percentile, at leastabout 99^(th) percentile, or at least about 100^(th) percentile,inclusive of all ranges and subranges therebetween, and any BMIpercentile described herein, and can be considered obese. In oneembodiment, the patient is about 5 to about 19 years old or about 7 toabout 18 years old.

In some embodiments, the patient treated according to the methods of thepresent disclosure is a female patient in the first trimester throughthird trimester of a pregnancy and has a BMI of at least 25 to at leastabout 29.9, at least about 25.5 to at least about 29, at least about 26to at least about 28.5, at least about 26.5 to at least about 28, or atleast about 27 to at least about 27.5, inclusive of all ranges andsubranges therebetween, and can be considered overweight or pre-obese.In some embodiments, the patient is a female patient in the firsttrimester through third trimester of a pregnancy and has a BMI of atleast about 30 to at least about 34.9, at least about 30.5 to at leastabout 34, at least about 31 to at least about 33.5, at least about 31.5to at least about 33, or at least about 32 to at least about 32.5,inclusive of all ranges and subranges therebetween, and can beconsidered obese. In some embodiments, the patent treated according tothe methods of the present invention is a female patient in the firsttrimester through third trimester of a pregnancy and has a BMI of atleast about 35 to at least about 39.9, at least about 35.5 to at leastabout 39, at least about 36 to at least about 38.5, at least about 36.5to at least about 38, at least about 37 to at least about 37.5,inclusive of all ranges and subranges therebetween, and can beconsidered severely obese.

In some embodiments, methods of calculating BMI may include, but are notlimited to body weight in kilogram/(height in meters)², body weight inpounds/(height in inches)²]×703, and the like.

In some embodiments, the patient treated according to the methods of thepresent disclosure can alternatively be described as having a % idealbody weight (% IBW) of at least about 110%, at least about 111%, atleast about 112%, at least about 113%, at least about 114%, at leastabout 115%, at least about 116%, at least about 117%, at least about118%, at least about 119%, at least about 120%, at least about 121%, atleast about 122%, at least about 123%, at least about 124%, at leastabout 125%, at least about 126%, at least about 127%, at least about128%, at least about 129%, at least about 130%, at least about 131%, atleast about 132%, at least about 133%, at least about 134%, at leastabout 135%, at least about 136%, at least about 137%, at least about138%, at least about 139%, at least about 140%, at least about 141%, atleast about 142%, at least about 143%, at least about 144%, at leastabout 145%, at least about 146%, at least about 147%, at least about148%, at least about 149%, at least about 150%, at least about 151%, atleast about 152%, at least about 153%, at least about 154%, at leastabout 155%, at least about 156%, at least about 157%, at least about158%, at least about 159%, at least about 160%, at least about 161%, atleast about 162%, at least about 163%, at least about 164%, at leastabout 165%, at least about 166%, at least about 167%, at least about168%, at least about 169%, at least about 170%, at least about 171%, atleast about 172%, at least about 173%, at least about 174%, at leastabout 175%, at least about 176%, at least about 177%, at least about178%, at least about 179%, at least about 180%, at least about 181%, atleast about 182%, at least about 183%, at least about 184%, at leastabout 185%, at least about 186%, at least about 187%, at least about188%, at least about 189%, at least about 190%, at least about 191%, atleast about 192%, at least about 193%, at least about 194%, at leastabout 195%, at least about 196%, at least about 197%, at least about198%, at least about 199%, at least about 200%, at least about 201%, atleast about 202%, at least about 203%, at least about 204%, at leastabout 205%, at least about 206%, at least about 207%, at least about208%, at least about 209%, at least about 210%, at least about 211%, atleast about 212%, at least about 213%, at least about 214%, at leastabout 215%, at least about 216%, at least about 217%, at least about218%, at least about 219%, at least about 220%, at least about 221%, atleast about 222%, at least about 223%, at least about 224%, at leastabout 225%, at least about 226%, at least about 227%, at least about228%, at least about 229%, at least about 230%, at least about 231%, atleast about 232%, at least about 233%, at least about 234%, at leastabout 235%, at least about 236%, at least about 237%, at least about238%, at least about 239%, at least about 240%, at least about 241%, atleast about 242%, at least about 243%, at least about 244%, at leastabout 245%, at least about 246%, at least about 247%, at least about248%, at least about 249%, at least about 250%, at least about 251%, atleast about 252%, at least about 253%, at least about 254%, at leastabout 255%, at least about 256%, at least about 257%, at least about258%, at least about 259%, at least about 260%, at least about 261%, atleast about 262%, at least about 263%, at least about 264%, at leastabout 265%, at least about 266%, at least about 267%, at least about268%, at least about 269%, at least about 270%, at least about 271%, atleast about 272%, at least about 273%, at least about 274%, at leastabout 275%, at least about 276%, at least about 277%, at least about278%, at least about 279%, or at least about 280%, inclusive of allranges and subranges therebetween, and any % ideal body weight describedherein. In one embodiment, the patient has % ideal body weight (IBW) ofat least about 150%. In one embodiment, the patient has % ideal bodyweight (IBW) of at least about 250%. In other embodiments, the patienthas % IBW of at least 150% and can be considered obese.

In some embodiments, the patient treated according to the presentdisclosure can alternatively be described as having a waist size orwaist circumference greater than about 32, greater than about 33,greater than about 34, greater than about 35 inches, greater than about36, greater than about 37, greater than about 38, greater than about 39,greater than about 40, greater than about 41, greater than about 42,greater than about 43, greater than about 44, greater than about 45,greater than about 46, greater than about 47, greater than about 48,greater than about 49, greater than about 50, greater than about 51,greater than about 52, greater than about 53, greater than about 54,greater than about 55, greater than about 56, greater than about 57,greater than about 58, greater than about 59, greater than about 60inches, greater than about 61 inches, greater than about 62 inches,greater than about 63 inches, greater than about 64 inches, greater thanabout 65 inches, inclusive of all ranges and subranges therebetween, andany waist size or circumference described herein. In one embodiment, apatient having a waist size or waist circumference of about 42 inchescan be considered obese. In another embodiment, the patient has waistsize or waist circumference greater than about 48 inches. In otherembodiment, the patient has waist or waist circumference of at least 42inches.

In some embodiments, the patient treated according to the methods of thepresent disclosure can alternatively be described as having a % body fatgreater than about 20%, greater than about 21%, greater than about 22%,greater than about 23%, greater than about 24%, greater than about 25%,greater than about 26%, greater than about 27%, greater than about 28%,greater than about 29%, greater than about 30%, greater than about 31%,greater than about 32%, greater than about 33%, greater than about 34%,greater than about 35%, greater than about 36%, greater than about 37%,greater than about 38%, greater than about 39%, greater than about 40%,greater than about 41%, greater than about 42%, greater than about 43%,greater than about 44%, greater than about 45%, greater than about 46%,greater than about 47%, greater than about 48%, greater than about 49%,or greater than about 50%, inclusive of all ranges and subrangestherebetween, and any % body fat described herein. In one embodiment,the patient has a % body fat greater than about 40%. In one embodiment,the patient has a % body fat of at least about 50%. In anotherembodiment, a patient having a % body fat greater than about 40% can beconsidered obese. In some embodiments, methods of calculating % body fatcan include, but are not limited to total body fat expressed as apercentage of total body weight. Other standards for obesity can beused. For example, the American Council on Exercise suggests that an“average” percentage of body fat for women is about 25-31%, and for men,about 18-24%, and for obese women, about 32% and higher, and obese men,about 25% and higher.

In other embodiments, the patient can alternatively be described ashaving a % android body fat greater than about 30%, greater than about31%, greater than about 32%, greater than about 33%, greater than about34%, greater than about 35%, greater than about 36%, greater than about37%, greater than about 38%, greater than about 39%, greater than about40%, greater than about 41%, greater than about 42%, greater than about43%, greater than about 44%, greater than about 45%, greater than about46%, greater than about 47%, greater than about 48%, greater than about49%, greater than about 50%, greater than about 51%, greater than about52%, greater than about 53%, greater than about 54%, greater than about55%, greater than about 56%, greater than about 57%, greater than about58%, greater than about 59%, greater than about 60%, greater than about61%, greater than about 62%, greater than about 63%, greater than about64%, greater than about 65%, greater than about 66%, greater than about67%, greater than about 68%, greater than about 69%, greater than about70%, greater than about 71%, greater than about 72%, greater than about73%, greater than about 74%, greater than about 75%, greater than about76%, greater than about 77%, greater than about 78%, greater than about79%, or greater than about 80%, inclusive of all ranges and subrangestherebetween, and any % android body fat described herein. In oneembodiment, a patient having a % android body fat greater than about 40%can be considered obese. In one embodiment, a patient having a % androidbody fat greater than about 50% can be considered obese

In other embodiments, the patient can alternatively be described ashaving a % android body fat of at least about 30%, at least about 31%,at least about 32%, at least about 33%, at least about 34%, at leastabout 35%, at least about 36%, at least about 37%, at least about 38%,at least about 39%, at least about 40%, at least about 41%, at leastabout 42%, at least about 43%, at least about 44%, at least about 45%,at least about 46%, at least about 47%, at least about 48%, at leastabout 49%, at least about 50%, at least about 51%, at least about 52%,at least about 53%, at least about 54%, at least about 55%, at leastabout 56%, at least about 57%, at least about 58%, at least about 59%,at least about 60%, at least about 61%, at least about 62%, at leastabout 63%, at least about 64%, at least about 65%, at least about 66%,at least about 67%, at least about 68%, at least about 69%, at leastabout 70%, at least about 71%, at least about 72%, at least about 73%,at least about 74%, at least about 75%, at least about 76%, at leastabout 77%, at least about 78%, at least about 79%, or at least about80%, inclusive of all ranges and subranges therebetween, and % androidbody fat described herein. In one embodiment, the patient has % androidbody fat of at least about 50%.

In other embodiments, the patient can alternatively be described ashaving a % gynoid body fat greater than about 30%, greater than about31%, greater than about 32%, greater than about 33%, greater than about34%, greater than about 35%, greater than about 36%, greater than about37%, greater than about 38%, greater than about 39%, greater than about40%, greater than about 41%, greater than about 42%, greater than about43%, greater than about 44%, greater than about 45%, greater than about46%, greater than about 47%, greater than about 48%, greater than about49%, greater than about 50%, greater than about 51%, greater than about52%, greater than about 53%, greater than about 54%, greater than about55%, greater than about 56%, greater than about 57%, greater than about58%, greater than about 59%, greater than about 60%, greater than about61%, greater than about 62%, greater than about 63%, greater than about64%, greater than about 65%, greater than about 66%, greater than about67%, greater than about 68%, greater than about 69%, greater than about70%, greater than about 71%, greater than about 72%, greater than about73%, greater than about 74%, greater than about 75%, greater than about76%, greater than about 77%, greater than about 78%, greater than about79%, or greater than about 80%, inclusive of all ranges and subrangestherebetween, and any % gynoid body fat described herein. In oneembodiment, a patient having a % gynoid body fat greater than about 40%can be considered obese. In one embodiment, a patient having a % gynoidbody fat greater than about 50% can be considered obese.

In other embodiments, the patient can alternatively be described ashaving a total body fat content greater than about 30 kg, greater thanabout 31 kg, greater than about 32 kg, greater than about 33 kg, greaterthan about 34 kg, greater than about 35 kg, greater than about 36 kg,greater than about 37 kg, greater than about 38 kg, greater than about39 kg, greater than about 40 kg, greater than about 41 kg, greater thanabout 42 kg, greater than about 43 kg, greater than about 44 kg, greaterthan about 45 kg, greater than about 46 kg, greater than about 47 kg,greater than about 48 kg, greater than about 49 kg, greater than about50 kg, greater than about 51 kg, greater than about 52 kg, greater thanabout 53 kg, greater than about 54 kg, greater than about 55 kg, greaterthan about 56 kg, greater than about 57 kg, greater than about 58 kg,greater than about 59 kg, greater than about 60 kg, greater than about61 kg, greater than about 62 kg, greater than about 63 kg, greater thanabout 64 kg, greater than about 65 kg, greater than about 66 kg, greaterthan about 67 kg, greater than about 68 kg, greater than about 69 kg,greater than about 70 kg, greater than about 71 kg, greater than about72 kg, greater than about 73 kg, greater than about 74 kg, greater thanabout 75 kg, greater than about 76 kg, greater than about 77 kg, greaterthan about 78 kg, greater than about 79 kg, greater than about 80 kg,greater than about 81 kg, greater than about 82 kg, greater than about83 kg, greater than about 84 kg, greater than about 85 kg, greater thanabout 86 kg, greater than about 87 kg, greater than about 88 kg, greaterthan about 89 kg, greater than about 90 kg, greater than about 91 kg,greater than about 92 kg, greater than about 93 kg, greater than about94 kg, greater than about 95 kg, greater than about 96 kg, greater thanabout 97 kg, greater than about 98 kg, greater than about 99 kg, greaterthan about 100 kg, at least 101 kg, at least 102 kg, at least 103 kg, atleast 104 kg, at least 105 kg, at least 106 kg, at least 107 kg, atleast 108 kg, at least 109 kg, or at least 110 kg, inclusive of allranges and subranges therebetween, and any total body fat describedherein. In one embodiment, a patient having total body fat greater thanabout 40 kg can be considered obese. In one embodiment, a patient havingtotal body fat greater than about 50 kg can be considered obese.

In other embodiments, the obesity status of patients treated with themethods of the present disclosure can be measured by waist-to-hip ratio.In other embodiments, the obesity status of patients can be measured byskinfold thickness. In other embodiments, the obesity status of patientscan be measured by bioelectric impedance. In other embodiments, theobesity status of patients can be measured by underwater weighing ordensitometry. In other embodiments, the obesity status of patients canbe measured by air-displacement plethysmography. In other embodiments,the obesity status of patients can be measured by dilution method orhydrometry. In other embodiments, the obesity status of patients can bemeasured by dual energy X-ray absorptiometry. In other embodiments, theobesity status of patients can be measured by computerized tomographyand magnetic resonance imaging. In some embodiments, the obesity statuscan be defined by, but is not limited to adopting the clinicalstandards, conventional standards, and/or the standards published by theWorld Health Organization and Center of Disease Control (both of whichare herein incorporated by reference in their entireties for allpurposes) when using the methods described herein. For example, the WHOdefines an obese person as a person with a BMI of 30 or more, anoverweight person is one with a BMI equal to or more than 25 (to lessthan 30). Similarly, the CDC defines normal as a BMI of 18.5 to lessthan 25, 25.0 to less than 30 as overweight, and 30.0 or higher asobese. The CDC further subdivides obesity into 3 classes: Class 1, a BMIof 30 to less than 35; Class 2, a BMI of 35 to less than 40; and Class3, as a BMI of 40 or higher. The CDC sometimes refers to Class 3 obesityas “extreme” or “severe” obesity.

In some embodiments, the patient treated by the methods of the presentdisclosure can be characterized by two or more of the physiologicalcharacteristics described herein. For example the patient can have a BMIof at least about 35 and can have a % IBW of at least 150%. In someembodiments, the patient can have a BMI of at least about 35 and canhave a waist size greater than about 42 inches. In some embodiments, thepatient can have a BMI of at least about 35 and can have a % body fatgreater than about 40%. In some embodiments, the patient can have a BMIof at least about 35 and can have a % android body fat greater thanabout 40%. In some embodiments, the patient can have a BMI of at leastabout 35 and can have a % gynoid body fat greater than about 40%. Insome embodiments, the patient can have a BMI of at least about 35 andcan have total body fat greater than about 40 kg. In various otherembodiments, the patient can have any combination of two or more of anyof the specific physiological parameters described herein.

In some embodiments, the patient can have three or more of thephysiological parameters described herein, for example a BMI of at leastabout 35, a % IBW of at least 150%, and waist size greater than about 42inches. In some embodiments, the patient can have a BMI of at leastabout 35, a % IBW of at least 150%, and a % body fat greater than about40%. In some embodiments, the patient can have a BMI of at least about35, a % IBW of at least 150%, and a % android body fat greater thanabout 40%. In some embodiments, the patient can have a BMI of at leastabout 35, a % IBW of at least 150%, and a % gynoid body fat greater thanabout 40%. In some embodiments, the patient can have a BMI of at leastabout 35, a % IBW of at least 150%, and total body fat greater thanabout 40 kg. In various other embodiments, the patient can have anycombination of three or more of any of the specific physiologicalparameters described herein.

In some embodiments, the patient can have four or more of thephysiological parameters described herein, for example the patient canhave a BMI of at least about 35, a % IBW of at least 150%, waist sizegreater than about 42 inches, and a % body fat greater than about 40%.In some embodiments, the patient can have a BMI of at least about 35, a% IBW of at least 150%, waist size greater than about 42 inches, and a %android body fat greater than about 40%. In some embodiments, thepatient can have a BMI of at least about 35, a % IBW of at least 150%,waist size greater than about 42 inches, and a % gynoid body fat greaterthan about 40%. In some embodiments, the patient can have a BMI of atleast about 35, a % IBW of at least 150%, a waist size greater thanabout 42 inches, and total body fat greater than about 43 kg. In some aembodiments, the patient can have a BMI of at least about 35, a % IBW ofat least 150%, a waist size greater than about 42 inches, a % body fatgreater than about 40%, and a % android body fat greater than about 40%.In some embodiments, the patient can have a BMI of at least about 35, a% IBW of at least 150%, a waist size greater than about 42 inches, a %body fat greater than about 40%, and a % gynoid body fat greater thanabout 40%. In some embodiments, the patient can have a BMI of at leastabout 35, a % IBW of at least 150%, a waist size greater than about 42inches, a % body fat greater than about 40%, and total body fat greaterthan about 40 kg. In some embodiments, the patient can have a BMI of atleast about 35, a % IBW of at least 150%, a waist size greater thanabout 42 inches, a % body fat greater than about 40%, a % android bodyfat greater than about 40%, in % gynoid body fat greater than about 40%,and total body fat greater than about 40 kg. In one embodiment, thepatient who has a BMI of at least about 35, in % IBW of at least 150%, awaist size greater than about 42 inches, and a % body fat greater thanabout 40%, a % android body fat greater than about 40%, a % gynoid bodyfat greater than about 40%, and total body fat greater than about 40 kg.In various other embodiments, the patient can have any combination ofany or all of the specific physiological parameters described herein.

In some embodiments, the patient can have a waist size greater thanabout 42 inches, a % body fat greater than about 40%, and a % androidbody fat greater than about 40%. In some embodiments, the patient canhave a waist size greater than about 42 inches, a % body fat greaterthan about 40%, and a % gynoid body fat greater than about 40%. In someembodiments, the patient can have a waist size greater than about 42inches, a % body fat greater than about 40%, and total body fat greaterthan about 40 kg.

In some embodiments, the patient can have a % body fat greater thanabout 40%, a % android body fat greater than about 40%, and a % gynoidbody fat greater than about 40%. In some embodiments, the patient canhave a % body fat greater than about 40%, a % android body fat greaterthan about 40%, and total body fat greater than about 40 kg. In someembodiments, the patient can have a % body fat greater than about 40%, a% gynoid body fat greater than about 40%, and total body fat greaterthan about 40 kg. In some embodiments, a % android body fat greater thanabout 40%, and a % gynoid body fat greater than about 40%, and totalbody fat greater than about 43 kg. In some embodiments, the patient canhave any combinations of obesity characteristics described herein

In some embodiments, patients with at least one of the obesitycharacteristics described herein can be an intermediate CYP3A4metabolizer. In other embodiments, the patients with at least one of theobesity characteristics described herein can be a poor CYP3A4metabolizer. In some embodiments, the patients with at least one of theobesity characteristics described herein can be an extensive CYP3A4metabolizer. In still other embodiments, the patient is not obese, e.g.,can have normal weight, and be an intermediate or poor CYP3A4metabolizer.

Alternatively, in some embodiments, the CYP3A4 genotype can be tested byusing targeted variant analysis. In some embodiments, the CYP3A4genotype can be tested by using sequence analysis of select exons.

In various embodiments, the present disclosure also provides for methodsof treating patients previously treated with posaconazole with a CYP3A4substrate drug which is contraindicated for concomitant use with astrong CYP3A4 inhibitor, such as posaconazole, wherein the CYP3A4substrate drug maintains an AUC which is no more than about 3000% of anormal baseline AUC (as defined above) of the CYP3A4 substrate drug,e.g., no more than about 2950%, no more than about 2900%, no more thanabout 2850%, no more than about 2800%, no more than about 2750%, no morethan about 2700%, no more than about 2650%, no more than about 2600%, nomore than about 2550%, no more than about 2500%, no more than about2450%, no more than about 2400%, no more than about 2350%, no more thanabout 2300%, no more than about 2250%, no more than about 2200%, no morethan about 2150%, no more than about 2100%, no more than about 2050%, nomore than about 2000%, no more than about 1950%, no more than about1900%, no more than about 1850%, no more than about 1800%, no more thanabout 1750%, no more than about 1700%, no more than about 1650%, no morethan about 1600%, no more than about 1550%, no more than about 1500%, nomore than about 1450%, no more than about 1400%, no more than about1350%, no more than about 1300%, no more than about 1250%, no more thanabout 1200%, no more than about 1150%, no more than about 1100%, no morethan about 1050%, no more than about 1000%, no more than about 950%, nomore than about 900%, no more than about 850%, no more than about 800%,no more than about 750%, no more than about 700%, no more than about650%, no more than about 600%, no more than about 550%, no more thanabout 500%, no more than about 450%, no more than about 445%, no morethan about 440%, no more than about 435%, no more than 430%, no morethan about 425%, no more than about 420%, no more than about 415%, nomore than about 410%, no more than about 405%, no more than about 400%,no more than about 395%, no more than about 390%, no more than about385%, no more than about 380%, no more than about 375%, no more thanabout 370%, no more than about 365%, no more than about 360%, no morethan about 355%, no more than about 350%, no more than about 345%, nomore than about 340%, no more than about 335%, no more than 330%, nomore than about 325%, no more than about 320%, no more than about 315%,no more than about 310%, no more than about 305%, or no more than about300%, no more than about 295%, no more than about 290%, no more thanabout 285%, no more than about 280%, no more than about 275%, no morethan about 270%, no more than about 265%, no more than about 260%, nomore than about 255%, no more than about 250%, no more than about 245%,no more than about 240%, no more than about 235%, no more than 230%, nomore than about 225%, no more than about 220%, no more than about 216%,no more than about 215%, no more than about 210%, no more than about205%, no more than about 200%, no more than about 195%, no more thanabout 190%, no more than about 185%, no more than about 180%, no morethan about 175%, no more than about 170%, no more than about 165%, nomore than about 160%, no more than about 155%, no more than about 150%,no more than about 145%, no more than about 140%, no more than about135%, no more than about 130%, no more than about 125%, no more thanabout 120%, no more than about 115%, no more than about 110%, no morethan about 105%, or no more than about 100% of the normal baseline AUCof the CYP3A4 substrate drug, inclusive of all ranges and subrangestherebetween. In particular embodiments, the CYP3A4 substrate drug isranolazine, and the AUC of ranolazine is maintained at a level of nomore than about 150% of a normal baseline AUC of ranolazine. As usedherein, the “normal baseline AUC of ranolazine” refers to the steadystate AUC₀₋₁₂ measured for a particular dose of ranolazine in theabsence of other drugs. In some embodiments, the steady state AUC₀₋₁₂ (%CV) is 13,720 (670.0%) ng*h/mL measured after administration of 500 mgranolazine. In some embodiments, the steady state AUC₀₋₁₂ (% CV) is32,091 (42.2%) ng*h/mL measured after administration of 1,000 mgranolazine. In other particular embodiments, the CYP3A4 substrate drugis lurasidone, and the AUC of lurasidone is maintained at a level of nomore than about 216% of a normal baseline AUC of lurasidone. As usedherein, the “normal baseline AUC of lurasidone” refers to the meanAUC_(0-tau) measured for a particular dose of lurasidone in the absenceof other drugs. In some embodiments, the mean AUC_(0-tau) is about 743ng*h/mL measured after administration of 120 mg lurasidone administeredin the fed state after a 350 kcal meal. In other particular embodiments,the CYP3A4 drug is tadalafil, and the AUC of tadalafil is maintained ata level of no more than about 410% of a normal baseline AUC oftadalafil. As used herein, the “normal baseline AUC of tadalafil” refersto the mean AUC_(0-∞) (% CV) measured for a particular dose of tadalafilin the absence of other drugs. In some embodiments, the mean AUC_(0-∞)(% CV) is about 3647 (34.0%) μg*h/L measured after administration of 10mg tadalafil. In some embodiments, the mean AUC_(0-∞) (% CV) is about13,006 (43.9%) μg*h/L for 20 mg tadalafil. In some embodiments, the meanAUC_(0-∞) (% CV) is within the range of about 7,000 to about 13,000(40.0%) μg*h/L for 20 mg tadalafil. In other particular embodiments, theCYP3A4 drug is erlotinib, and the AUC of erlotinib is maintained at alevel of no more than about 164% of a normal baseline AUC of erlotinibat 150 mg. As used herein, the “normal baseline AUC of erlotinib” refersto the mean AUC₀₋₂₄ (% CV) measured for a particular dose of erlotinibin the absence of other drugs. In some embodiments, the mean AUC₀₋₂₄ (%CV) at steady state is about 15.2 (400.0%) μg*h/mL measured afteradministration of 150 mg erlotinib. The AUC₀₋₂₄ of erlotinib is highlyvariable and tends to increase in cancer patients relative to healthyvolunteers. Thus, in some embodiments, the mean AUC₀₋₂₄ (% CV) can rangefrom about 1 μg*h/mL to about 35 μg*h/mL, e.g., about 2 μg*h/mL, about 3μg*h/mL, about 4 μg*h/mL, about 5 μg*h/mL, about 6 μg*h/mL, about 7μg*h/mL, about 8 μg*h/mL, about 9 μg*h/mL, about g*h/mL, about 11μg*h/mL, about 12 μg*h/mL, about 13 μg*h/mL, about 14 μg*h/mL, aboutg*h/mL, about 16 μg*h/mL, about 17 μg*h/mL, about 18 μg*h/mL, about 19μg*h/mL, about g*h/mL, about 21 μg*h/mL, about 22 μg*h/mL, about 23μg*h/mL, about 24 μg*h/mL, about g*h/mL, about 27 μg*h/mL, about 28μg*h/mL, about 29 μg*h/mL, about 30 μg*h/mL, about 31 μg*h/mL, about 32μg*h/mL, about 33 μg*h/mL, about 34 μg*h/mL, about 35 μg*h/mL, about 36μg*h/mL, about 37 μg*h/mL, about 38 μg*h/mL, about 39 μg*h/mL, about 40μg*h/mL, about 41 μg*h/mL, about 42 μg*h/mL, about 43 μg*h/mL, about 44μg*h/mL, about 45 μg*h/mL, about 47 μg*h/mL, about 48 μg*h/mL, about 49μg*h/mL, about 50 μg*h/mL, about 51 μg*h/mL, about 52 μg*h/mL, about 53μg*h/mL, about 54 μg*h/mL, about 55 μg*h/mL, about 57 μg*h/mL, about 58μg*h/mL, about 59 μg*h/mL, about 60 μg*h/mL, inclusive of all values andsubranges therebetween. In other particular embodiments, the CYP3A4 drugis solifenacin succinate, and the AUC of solifenacin succinate ismaintained at a level of no more than about 270% of a normal baselineAUC of solifenacin succinate. As used herein, the “normal baseline AUCof solifenacin succinate” refers to the mean AUC₀₋₂₄ (% CV) at steadystate measured for a particular dose of solifenacin succinate in theabsence of other drugs. In some embodiments, the mean AUC₀₋₂₄ (% CV) atsteady state is about 463 (37%) ng*h/mL for 5 mg solifenacin succinate.In some embodiments, the mean AUC₀₋₂₄ (% CV) at steady state is about749 (22%) ng*h/mL for 10 mg solifenacin succinate. In other particularembodiments, the CYP3A4 drug is everolimus, and the AUC of everolimus ismaintained at a level of no more than about 440% of a normal baselineAUC of everolimus. As used herein, the “normal baseline AUC ofeverolimus” refers to the mean AUC₀₋₂₄±SD measured at steady stateconditions for a particular dose of everolimus in the absence of otherdrugs. In some embodiments, the mean AUC₀₋₂₄+SD is about 536±7.7 ng*h/mLmeasured after administration of 10 mg everolimus.

In various other embodiments, the present disclosure provides formethods of treating patients previously treated with posaconazole,comprising treating or prescribing a reduced dose of a CYP3A4 substratedrug which is contraindicated for concomitant use with a strong CYP3A4inhibitor (e.g., about 10%-90%, of the reference dose) for a period ofabout 2-42 days after stopping posaconazole treatment as describedherein, wherein the CYP3A4 substrate drug is maintained an AUC which isno more than about 3000% of the baseline AUC of the CYP3A4 substratedrug, e.g., no more than about 2950%, no more than about 2900%, no morethan about 2850%, no more than about 2800%, no more than about 2750%, nomore than about 2700%, no more than about 2650%, no more than about2600%, no more than about 2550%, no more than about 2500%, no more thanabout 2450%, no more than about 2400%, no more than about 2350%, no morethan about 2300%, no more than about 2250%, no more than about 2200%, nomore than about 2150%, no more than about 2100%, no more than about2050%, no more than about 2000%, no more than about 1950%, no more thanabout 1900%, no more than about 1850%, no more than about 1800%, no morethan about 1750%, no more than about 1700%, no more than about 1650%, nomore than about 1600%, no more than about 1550%, no more than about1500%, no more than about 1450%, no more than about 1400%, no more thanabout 1350%, no more than about 1300%, no more than about 1250%, no morethan about 1200%, no more than about 1150%, no more than about 1100%, nomore than about 1050%, no more than about 1000%, no more than about950%, no more than about 900%, no more than about 850%, no more thanabout 800%, no more than about 750%, no more than about 700%, no morethan about 650%, no more than about 600%, no more than about 550%, nomore than about 500%, no more than about 450%, no more than about 445%,no more than about 440%, no more than about 435%, no more than 430%, nomore than about 425%, no more than about 420%, no more than about 415%,no more than about 410%, no more than about 405%, no more than about400%, no more than about 395%, no more than about 390%, no more thanabout 385%, no more than about 380%, no more than about 375%, no morethan about 370%, no more than about 365%, no more than about 360%, nomore than about 355%, no more than about 350%, no more than about 345%,no more than about 340%, no more than about 335%, no more than 330%, nomore than about 325%, no more than about 320%, no more than about 315%,no more than about 310%, no more than about 305%, or no more than about300%, no more than about 295%, no more than about 290%, no more thanabout 285%, no more than about 280%, no more than about 275%, no morethan about 270%, no more than about 265%, no more than about 260%, nomore than about 255%, no more than about 250%, no more than about 245%,no more than about 240%, no more than about 235%, no more than 230%, nomore than about 225%, no more than about 220%, no more than about 216%,no more than about 215%, no more than about 210%, no more than about205%, no more than about 200%, no more than about 195%, no more thanabout 190%, no more than about 185%, no more than about 180%, no morethan about 175%, no more than about 170%, no more than about 165%, nomore than about 160%, no more than about 155%, no more than about 150%,no more than about 145%, no more than about 140%, no more than about135%, no more than about 130%, no more than about 125%, no more thanabout 120%, no more than about 115%, no more than about 110%, no morethan about 105%, or no more than about 100% of the normal baseline AUCof the CYP3A4 substrate drug, inclusive of all ranges and subrangestherebetween. In particular embodiments, the CYP3A4 substrate drug isranolazine, and the AUC of ranolazine is maintained at a level of nomore than about 150% of the normal baseline AUC of ranolazine. In otherparticular embodiments, the CYP3A4 substrate drug is lurasidone, and theAUC of lurasidone is maintained at a level of no more than about 216% ofthe normal baseline AUC of lurasidone. In other particular embodiments,the CYP3A4 substrate drug is tadalafil, and the AUC of tadalafil ismaintained at a level of no more than about 410% of the normal baselineAUC of tadalafil. In other particular embodiments, the CYP3A4 substratedrug is tadalafil, and the AUC of tadalafil is maintained at a level ofno more than about 260% of the normal baseline AUC of tadalafil. Inother particular embodiments, the CYP3A4 substrate drug is tadalafil,and the AUC of tadalafil is maintained at a level of no more than about207% of the normal baseline AUC of tadalafil. In other particularembodiments, the CYP3A4 substrate drug is erlotinib, and the AUC oferlotinib is maintained at a level of no more than about 164% of thenormal baseline AUC of erlotinib. In other particular embodiments, theCYP3A4 substrate drug is solifenacin succinate, and the AUC ofsolifenacin succinate is maintained at a level of no more than about270% of the normal baseline AUC of solifenacin succinate. In otherparticular embodiments, the CYP3A4 substrate drug is everolimus, and theAUC of everolimus is maintained at a level of no more than about 440% ofthe normal baseline AUC of everolimus.

In various embodiments, the present disclosure also provides for methodsof treating patients previously treated with posaconazole, with a CYP3A4substrate drug which is contraindicated for concomitant use with astrong CYP3A4 inhibitor, such as posaconazole, wherein the CYP3A4substrate drug maintains a C_(max) which is no more than about 4000% ofthe normal baseline C_(max) of the CYP3A4 substrate drug, e.g., 3950%,no more than about 3900%, no more than about 3850%, no more than about3800%, no more than about 3750%, no more than about 3700%, no more thanabout 3650%, no more than about 3600%, no more than about 3550%, no morethan about 3500%, no more than about 3450%, no more than about 3400%, nomore than about 3350%, no more than about 3300%, no more than about3250%, no more than about 3200%, no more than about 3150%, no more thanabout 3100%, no more than about 3050%, no more than about 3000%, no morethan about 2950%, no more than about 2900%, no more than about 2850%, nomore than about 2800%, no more than about 2750%, no more than about nomore than about 2700%, no more than about 2650%, no more than about2600%, no more than about 2550%, no more than about 2500%, no more thanabout 2450%, no more than about 2400%, no more than about 2350%, no morethan about 2300%, no more than about 2250%, no more than about 2200%, nomore than about 2150%, no more than about 2100%, no more than about2050%, no more than about 2000%, no more than about 1950%, no more thanabout 1900%, no more than about 1850%, no more than about 1800%, no morethan about 1750%, no more than about 1700%, no more than about 1650%, nomore than about 1600%, no more than about 1550%, no more than about1500%, no more than about 1450%, no more than about 1400%, no more thanabout 1350%, no more than about 1300%, no more than about 1250%, no morethan about 1200%, no more than about 1150%, no more than about 1100%, nomore than about 1050%, no more than about 1000%, no more than about950%, no more than about 900%, no more than about 850%, no more thanabout 800%, no more than about 750%, no more than about 700%, no morethan about 650%, no more than about 600%, no more than about 550%, nomore than about 500%, no more than about 450%, no more than about 445%,no more than about 440%, no more than about 435%, no more than 430%, nomore than about 425%, no more than about 420%, no more than about 415%,no more than about 410%, no more than about 405%, no more than about400%, no more than about 395%, no more than about 390%, no more thanabout 385%, no more than about 380%, no more than about 375%, no morethan about 370%, no more than about 365%, no more than about 360%, nomore than about 355%, no more than about 350%, no more than about 345%,no more than about 340%, no more than about 335%, no more than 330%, nomore than about 325%, no more than about 320%, no more than about 315%,no more than about 310%, no more than about 305%, or no more than about300%, no more than about 295%, no more than about 290%, no more thanabout 285%, no more than about 280%, no more than about 275%, no morethan about 270%, no more than about 265%, no more than about 260%, nomore than about 255%, no more than about 250%, no more than about 245%,no more than about 240%, no more than about 235%, no more than 230%, nomore than about 225%, no more than about 220%, no more than about 216%,no more than about 215%, no more than about 210%, no more than about205%, no more than about 200%, no more than about 195%, no more thanabout 190%, no more than about 185%, no more than about 180%, no morethan about 175%, no more than about 170%, no more than about 165%, nomore than about 160%, no more than about 155%, no more than about 150%,no more than about 145%, no more than about 140%, no more than about135%, no more than about no130%, no more than about 125%, no more thanabout 120%, no more than about 115%, no more than about 110%, no morethan about 105%, or no more than about 100% inclusive of all ranges andsubranges therebetween. In particular embodiments, the CYP3A4 substratedrug is ranolazine, and the C_(max) of ranolazine is maintained at alevel of no more than about 150% of the normal baseline C_(max) ofranolazine. As used herein, the “normal baseline C_(max) of ranolazine”refers to the steady state C_(max) measured for a particular dose ofranolazine in the absence of other drugs. In some embodiments, thesteady state C_(max) (% CV) is 1081 (490.1%) ng/mL measured afteradministration of 500 mg ranolazine. In some embodiments, the steadystate C_(max) (% CV) is 1955 (54.0%) ng/mL measured after administrationof 1,000 mg ranolazine. In other particular embodiments, the CYP3A4substrate drug is lurasidone, and the C_(max) of lurasidone ismaintained at a level of no more than about 210% of the normal baselineC_(max) of lurasidone. As used herein, the “normal baseline C_(max) oflurasidone” refers to the mean C_(max) measured for a particular dose oflurasidone in the absence of other drugs. In some embodiments, the meanC_(max) (% CV) is about 160 ng/mL measured after administration of 120mg lurasidone in the fed state following a 350 kcal meal. In otherparticular embodiments, the CYP3A4 substrate drug is tadalafil, and theC_(max) of tadalafil is maintained at a level of no more than about 120%of the normal baseline C_(max) of tadalafil. As used herein, the “normalbaseline C_(max) of tadalafil” refers to the mean C_(max) measured for aparticular dose of tadalafil in the absence of other drugs. In someembodiments, the mean C_(max) (% CV) is 190 (21.7%) g/L measured afteradministration of 10 mg tadalafil. In some embodiments, the mean C_(max)(% CV) is 548 (24.0%) g/L measured after administration of 20 mgtadalafil. In other particular embodiments, the CYP3A4 substrate drug iserlotinib, and the C_(max) of erlotinib is maintained at a level of nomore than about 167% of the normal baseline C_(max) of erlotinib at 150mg. As used herein, the “normal baseline C_(max) of erlotinib” refers tothe mean C_(max) measured at steady state conditions for a particulardose of erlotinib in the absence of other drugs. In some embodiments,the mean C_(max) (% CV) is 1.7 (90%) g/mL measured after administrationof 150 mg erlotinib. The C_(max) of erlotinib is highly variable andtends to increase in cancer patients relative to healthy volunteers.Thus, in some embodiments, the mean AUC₀₋₂₄ (% CV) can range from about1 g*h/mL to about 35 μg*h/mL, e.g., about 2 μg*h/mL, about 3 μg*h/mL,about 4 μg*h/mL, about g*h/mL, about 6 μg*h/mL, about 7 μg*h/mL, about 8μg*h/mL, about 9 μg*h/mL, about 10 g*h/mL, about 11 μg*h/mL, about 12μg*h/mL, about 13 μg*h/mL, about 14 μg*h/mL, about g*h/mL, about 16μg*h/mL, about 17 μg*h/mL, about 18 μg*h/mL, about 19 μg*h/mL, aboutg*h/mL, about 21 μg*h/mL, about 22 μg*h/mL, about 23 μg*h/mL, about 24μg*h/mL, about g*h/mL, about 27 μg*h/mL, about 28 μg*h/mL, about 29μg*h/mL, about 30 μg*h/mL, about 31 μg*h/mL, about 32 μg*h/mL, about 33μg*h/mL, about 34 μg*h/mL, inclusive of all values and subrangestherebetween. In other particular embodiments, the CYP3A4 substrate drugis solifenacin succinate, and the C_(max) of solifenacin succinate ismaintained at a level of no more than about 150% of the normal baselineC_(max) of solifenacin succinate. As used herein, the “normal baselineC_(max) of solifenacin” refers to the mean C_(max) measured at steadystate conditions for a particular dose of solifenacin succinate in theabsence of other drugs. In some embodiments, the mean C_(max) (% CV) is24.01 (30%) ng/mL measured after administration of 5 mg solifenacin. Insome embodiments, the mean C_(max) (% CV) is 40.61 (21%) ng/mL measuredafter administration of 10 mg solifenacin succinate. In other particularembodiments, the CYP3A4 substrate drug is everolimus, and the C_(max) ofeverolimus is maintained at a level of no more than about 200% of thenormal baseline C_(max) of everolimus. As used herein, the “normalbaseline C_(max) of everolimus” refers to the mean C_(max) measured atsteady state conditions for a particular dose of everolimus in theabsence of other drugs. In some embodiments, the mean C_(max) (% CV) is59.7±16.9 (21.7%) ng/mL measured after administration of 10 mgeverolimus.

In various other embodiments, the present disclosure provides formethods of treating patients previously administered posaconazole with areduced dose of a CYP3A4 substrate drug (e.g., about 10%-50% of thereference dose) which is contraindicated for concomitant use with astrong CYP3A4 inhibitor, wherein the CYP3A4 substrate drug is maintainedat a dose which provides a C_(max) which is no more than about 4000% ofthe normal baseline C_(max) of the CYP3A4 substrate drug for a period ofat least about 2 to at least about 42 days after stopping posaconazoletreatment, e.g., 3950%, no more than about 3900%, no more than about3850%, no more than about 3800%, no more than about 3750%, no more thanabout 3700%, no more than about 3650%, no more than about 3600%, no morethan about 3550%, no more than about 3500%, no more than about 3450%, nomore than about 3400%, no more than about 3350%, no more than about3300%, no more than about 3250%, no more than about 3200%, no more thanabout 3150%, no more than about 3100%, no more than about 3050%, no morethan about 3000%, no more than about 2950%, no more than about 2900%, nomore than about 2850%, no more than about 2800%, no more than about2750%, no more than about no more than about 2700%, no more than about2650%, no more than about 2600%, no more than about 2550%, no more thanabout 2500%, no more than about 2450%, no more than about 2400%, no morethan about 2350%, no more than about 2300%, no more than about 2250%, nomore than about 2200%, no more than about 2150%, no more than about2100%, no more than about 2050%, no more than about 2000%, no more thanabout 1950%, no more than about 1900%, no more than about 1850%, no morethan about 1800%, no more than about 1750%, no more than about 1700%, nomore than about 1650%, no more than about 1600%, no more than about1550%, no more than about 1500%, no more than about 1450%, no more thanabout 1400%, no more than about 1350%, no more than about 1300%, no morethan about 1250%, no more than about 1200%, no more than about 1150%, nomore than about 1100%, no more than about 1050%, no more than about1000%, no more than about 950%, no more than about 900%, no more thanabout 850%, no more than about 800%, no more than about 750%, no morethan about 700%, no more than about 650%, no more than about 600%, nomore than about 550%, no more than about 500%, no more than about 450%,no more than about 445%, no more than about 440%, no more than about435%, no more than 430%, no more than about 425%, no more than about420%, no more than about 415%, no more than about 410%, no more thanabout 405%, no more than about 400%, no more than about 395%, no morethan about 390%, no more than about 385%, no more than about 380%, nomore than about 375%, no more than about 370%, no more than about 365%,no more than about 360%, no more than about 355%, no more than about350%, no more than about 345%, no more than about 340%, no more thanabout 335%, no more than 330%, no more than about 325%, no more thanabout 320%, no more than about 315%, no more than about 310%, no morethan about 305%, or no more than about 300%, no more than about 295%, nomore than about 290%, no more than about 285%, no more than about 280%,no more than about 275%, no more than about 270%, no more than about265%, no more than about 260%, no more than about 255%, no more thanabout 250%, no more than about 245%, no more than about 240%, no morethan about 235%, no more than 230%, no more than about 225%, no morethan about 220%, no more than about 216%, no more than about 215%, nomore than about 210%, no more than about 205%, no more than about 200%,no more than about 195%, no more than about 190%, no more than about185%, no more than about 180%, no more than about 175%, no more thanabout 170%, no more than about 165%, no more than about 160%, no morethan about 155%, no more than about 150%, no more than about 145%, nomore than about 140%, no more than about 135%, no more than about 130%,no more than about 125%, no more than about 120%, no more than about115%, no more than about 110%, no more than about 105%, or no more thanabout 100% inclusive of all ranges and subranges therebetween. Inparticular embodiments, the CYP3A4 substrate drug is ranolazine, and theC_(max) of ranolazine is maintained at a level of no more than about150% of the normal baseline C_(max) of ranolazine. In other particularembodiments, the CYP3A4 substrate drug is lurasidone, and the C_(max) oflurasidone is maintained at a level of no more than about 210% of thenormal baseline C_(max) of lurasidone. In other particular embodiments,the CYP3A4 substrate drug is tadalafil, and the C_(max) of tadalafil ismaintained at a level of no more than about 120% of the normal baselineC_(max) of tadalafil. In other particular embodiments, the CYP3A4substrate drug is erlotinib, and the C_(max) erlotinib is maintained ata level of no more than about 167% of the normal baseline C_(max) oferlotinib. In other particular embodiments, the CYP3A4 substrate drug issolifenacin succinate, and the C_(max) of solifenacin succinate ismaintained at a level of no more than about 150% of the normal baselineC_(max) of solifenacin succinate. In other particular embodiments, theCYP3A4 substrate drug is everolimus, and the C_(max) of everolimus ismaintained at a level of no more than about 200% of the normal baseline

CYP3A4 substrate drugs (such as lurasidone and ranolazine) have labelswhich contraindicate their coadministration with strong CYP3A4inhibitors, such as posaconazole. Thus, conventionally, it would beconsidered safe to administer the CYP3A4 substrate drug one day afterthe last dose of posaconazole (i.e., one day after discontinuing or“stopping” posaconazole). However, the interaction of posaconazole andmany CYP3A4 substrate drugs had not been investigated previously. TheApplicant's clinical research is the first work to observe the levels ofcertain CYP3A4 substrate drugs during both concomitant administration ofposaconazole and for an extended period after posaconazoleadministration has been stopped. Applicant discovered that theinhibitory effects of posaconazole on CYP3A4 last substantially longerthan would have been predicted from its half-life, and thus posaconazoleinhibits the metabolism of CYP3A4 substrate drugs for substantiallylonger than would have been predicted from the prior art. Thus, actualblood plasma levels of CYP3A4 substrate drugs are in fact significantlyhigher after stopping posaconazole than would have been predicted fromthe prior art. Therefore, in order to achieve a “safe” blood plasmaconcentration profile for the CYP3A4 substrate drug (e.g., when thebenefits of treating the patient for the condition or disease for whichthe CYP3A4 substrate drug is indicated outweigh the risks associatedwith the effects of a drug-drug interaction as described herein),Applicant discovered that patients must wait longer than previouslybelieved (e.g., more than the 1 day contraindication period provided bythe label), and/or administer a reduced dose of the CYP3A4 substratedrug.

For purposes of the present methods, the expected blood plasma levels ofa CYP3A4 substrate drug after stopping coadministration with a strongCYP3A4 inhibitor such as posaconazole or ketoconazole can be calculatedfrom the blood plasma levels of the CYP3A4 substrate drug duringcoadministration with the strong CYP3A4 inhibitor using conventionalpharmacological methods as described below. Blood plasma levels may bedescribed in various ways, such as area under the plasma concentrationcurve (AUC) and peak plasma concentration (C_(max)). Baseline levels andposaconazole interaction levels for CYP3A4 substrate drugs may becompared using the geometric mean ratio (GMR) of AUC and C_(max). Asused herein, “baseline” refers to the plasma concentration of the CYP3A4substrate drug in an otherwise identical patient population who has notbeen administered a CYP3A4 inhibitor drug. GMR is the standard industryand regulatory method for assessing the ratio of change of apharmacokinetic variable (such as AUC) relative to its own baselinevalue (e.g., in a patient that was not treated with posaconazole). Oncethe level of substrate drug (AUC or Cmax) during co-administration withposaconazole and a CYP3A4 substrate drug is known, a function can bederived using conventional pharmacological methods to estimate how theAUC or plasma level of the CYP3A4 substrate drug is expected to decayover time after stopping administration of posaconazole. Such a functioncan be used to provide a plot of the decay GMR of AUC (or Cmax) of theCYP3A4 substrate drug versus time due to its interaction withposaconazole, based on the stated half-life of posaconazole. As the GMRcurve approaches the time when the known half-life of posaconazolepredicts that essentially all of the posaconazole has been eliminated,the GMR approaches a value of 1.

One of ordinary skilled in the art would have understood that theexpected DDI decay curve could be calculated using equation 1 (Rang, H.,Dale, M., Ritter, J., and Flower R., Rang and Dale's Pharmacology, 6thed. London: Elsevier, Ltd 2007. Chapter 8, p. 122) to provide theexpected DDI decay curve:

AUC GMR at day(x)=1+[(AUC during co-administration)−1]*ê(−K _(el) *x)  (equation 1)

-   -   Where K_(el)=ln(2)/(31 hours/24 hours) or about 0.5366, based on        the 31 hour half-life of posaconazole tablets (Noxafil® label        updated 9/2016) and    -   Where x=the number of days after posaconazole discontinuation

The expected DDI decay curve can also be calculated for Cmax GMR bysubstituting Cmax during co-administration for AUC duringco-administration in equation 1. As used herein, “expected levels” and“predicted levels” and the like, refer to the AUC or Cmax GMR valuescalculated using equation 1.

Expected DDI curves have been prepared for lurasidone (FIG. 8; solidline) and ranolazine (FIG. 9; solid line), by applying equation 1 to AUClevels measured during coadministration with posaconazole. Clinicallyestablished coadministration levels have also been determined forencorafenib (BRAFTOVI®) in the presence of posaconazole. As shown inTable A, when coadministered with posaconazole, the drug-druginteraction with posaconazole elevates the baseline AUC of encorafenibby 300% (see column titled “AUC co-administration levels” “percent ofbaseline”). Equation 1 was applied to the coadministration AUC levelsfor encorafenib, and the predicted curve of posaconazole impact onencorafenib GMR of AUC was calculated as shown in FIG. 10.

Applicant surprisingly and unexpectedly discovered that blood plasmalevels of CYP3A4 substrate drugs administered after stoppingposaconazole, were significantly elevated compared to the expectedlevels of such drugs calculated using equation 1. Thus, Applicantdiscovered that the inhibitory effects of posaconazole on CYP3A4substrate drugs persist far longer than were previously known, and thatadministering the full reference dose of the CYP3A4 substrate drug afterstopping posaconazole (e.g., as taught in the labels of the CYP3A4substrate drugs described herein) will actually achieve blood plasmalevels of the CYP3A4 substrate drug that are greater than the expectedlevels, for example as calculated using equation 1 (see FIGS. 8 and 9;dashed lines). To address the clinical impact of this unexpectedincrease in blood plasma levels, Applicant discovered that: (i) a fullreference dose of the CYP3A4 substrate drug should be administered twoor more days (e.g., as described herein) after stopping posaconazole toachieve safe plasma levels that are higher than would have beenpredicted; or (ii) a reduced dose of the CYP3A4 substrate drug should beadministered e.g. to achieve safe plasma levels of the drug that areapproximately equivalent (e.g., about 80-125%) to those expected from afull reference dose of the CYP3A4 substrate drug based on the aboveequation. The reduced dose of the CYP3A4 substrate drug may beadministered with posaconazole, the day after stopping posaconazole, ortwo or more days (e.g., as described herein) after stoppingposaconazole.

In some embodiments (e.g., when a full dose is administered two or moredays after stopping posaconazole or when a reduced dose is administeredas described herein), the blood plasma levels of the CYP3A4 substratedrug are therapeutic, and are at or below the target levels that areconsidered safe (i.e., wherein inhibition of CYP3A4 by posaconazolewould not present an unacceptable risk of serious side effects to thepatient). Turning to FIG. 10, a line showing target AUC GMR levels ofencorafenib that are considered safe according to some embodiments hasbeen overlaid on this figure. The present disclosure provides formethods of administering encorafenib to achieve blood plasma levels thatare greater than the expected levels but do not exceed the target safelevels. Accordingly, in various embodiments, the present methodscomprise: (i) administering the reference dose of a CYP3A4 substratedrug (such as encorafenib) at least 2 days (e.g., 2, 3, 4, 5, 6, 7, 8,9,10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27,28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, or 42 days)after stopping posaconazole to achieve blood plasma levels that areabove those that would be predicted from the expected curve (e.g., abovethe predicted blood plasma level curve by about 5%, about 10%, about15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%,about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about80%, about 85%, about 90%, about 95%, about 100%, about 105%, about110%, about 115%, about 120%, about 125%, about 130%, about 135%, about140% ut 145% 145%, about 150%, about 155%, about 160%, about 165%, about170%, about 175%, about 180%, about 185%, about 190%, or about 195%above predicted levels) but do not exceed the target safe levels) or(ii) administering a reduced dose to achieve the blood plasma levelsthat are greater than or equal to those calculated for the fullreference dose but do not exceed the target safe levels.

As for lurasidone, ranolazine, and encorafenib, the expected DDI decaycurves of the blood plasma levels for other CYP3A4 substrate drugs canbe calculated using, e.g., Equation 1, from the blood plasma levels ofthe CYP3A4 substrate drugs obtained during coadministration withposaconazole, and the conventionally understood half-life ofposaconazole. Table A, below, contains (a) the co-administration levelsfor CYP3A4 substrate drugs in the columns entitled “AUCco-administration levels” and “Cmax co-administration levels”; (b) “AUCtarget safe level” and “Cmax target safe level” (the levels at whichbenefits outweigh risks according to some embodiments); and (c)“baseline AUC” and “baseline Cmax” levels for CYP3A4 substrate drugsmeasured in a patient that was not previously treated with a strongCYP3A4 inhibitor (e.g., posaconazole). The columns entitled“Co-administration levels” provide the fold change or percent ofbaseline increase observed when the substrate drug was co-administeredwith a strong CYP3A4 inhibitor (e.g., ketoconazole). Becauseco-administration of many of these CYP3A4 substrate drugs with strongCYP3A4 inhibitors is contraindicated, the co-administration levelsrepresent unsafe Cmax and AUC levels. In various embodiments, the“Target safe levels” are non-limiting examples of the upper limit offold change or percent of baseline where in some embodiments thebenefits of treating the patient for the condition or disease for whichthe CYP3A4 substrate drug is indicated outweigh the risks associatedwith the effects of a drug-drug interaction. While Table A provides oneexample of a target safe level for each CYP3A4 substrate drug, each drugmay have more than one target safe level (e.g., depending on particularrisk/benefit considerations for different patient populations).“Baseline AUC” or “Baseline Cmax” denotes the plasma concentrations ofthe CYP3A4 substrate drug in an otherwise identical patient who has notbeen administered a strong CYP3A4 inhibitor drug. The coadministrationlevels reported in Table A were measured with either posaconazole,itraconazole, ritonavir, or ketoconazole. For purposes of the presentmethods, the blood plasma levels measured during coadministration of theCYP3A4 substrate drug with ketoconazole may be used to estimate theposaconazole DDI decay curve, e.g., using equation 1. In someembodiments, the present disclosure provides for methods ofadministering a CYP3A4 substrate drug to achieve blood plasma levelsthat are less than or equal to the target safe AUC and Cmax shown inTable A. In order to determine when blood plasma levels will be withinsafe and effective levels, such that the proper delay period and/orreduced dosing period can be calculated, blood plasma levels of theCYP3A4 substrate drug can be measured using routine methods known in theart (e.g., obtaining blood samples from a patient and measuring theblood plasma concentration of the CYP3A4 substrate drug using massspectrometry). The following sections discuss how Applicant's surprisingand unexpected information about CYP3A4 inhibition by posaconazolegleaned from Applicant's clinical research inform dosing of CYP3A4substrate drugs.

TABLE 1 Pharmacokinetic Parameters of CYP3A4 Substrate Drugs AUCco-administration levels AUC target safe level Baseline AUC (% CV)Percent of Percent of (ng*h/mL unless CYP3A4 drug Fold change baselineFold change baseline otherwise specified) abemaciclib 16 1600%  1.3 130%steady state AUC₀₋₂₄: 150 mg Q12H: 4280, 200 mg Q12H: 5520 apalutamide1.24 124% 60 mg steady state: 100 +/− 32 ug*h/mL aripiprazole 1.7 170%AUC₀₋₂₄, 3 mg steady state: 678 +/− 413 bosutinib 2 200% multiple 400 mgdoses: 2720 +/− 442; multiple 500 mg doses: 3650 +/− 425 brexpiprazole 2200% AUC_(inf) 1 mg tablet: 612 +/− 222; 2 mg: 1940 +/− 989; 4 mg: 2690+/− 1710 brigatinib 2.01 201% AUC0-t, steady state 90 mg: 8165 (57); 180mg: 20276 (56) cabazitaxel 1.25 125% 25 mg/m²q3w: 991 (34) cariprazine 4400% 3 mg steady state: 156 +/− 72; 6 mg steady state: 358 +/− 85.2cobimetinib 6.7 670% AUC0-24, steady state 60 mg: 4340 (61) copanlisib1.53 153% 0.8 mg/kg AUC0-25 steady state: 1570 +/− 338 crizotinib 1.57157% steady state at 250 mg BID: 3880 (36) dabrafenib 1.71 171% day 15150 mg BID: 2619 (76.7) daclatasvir 3 300% AUC0-24, steady state 60 mg:10973 +/− 5288 dapagliflozin/ saxagliptin: 367% saxagliptin: 78saxagliptin 3.67 deflazacort 3 300% single dose: 280 duvelisib 2 200%steady state 25 mg bid: 7.9 (77) ug*h/mL elbasvir/ EBR: 1.8; EBR: 180%;AUC0-24 EBR: 1920, grazoprevir GZR: 3.02 GBR: 302% GZR: 1420 encorafenib3 300% median, 450 mg steady state: 12700 (range 9230-228000)flibanserin 1.4 140% single 100 mg dose AUCinf: 1543 +/− 511 fluticasonefluticasone fluticasone fluticasone: propionate/ propionate: propionate:230/21: 799 pg*h/mL salmeterol 1.9; 190%; after 2 inhalations, xinafoatesalmeterol: salmeterol: 115/21: 274 pg*h/mL, 15.76 1576% 45/21: 138pg*h/mL with a spacer; salmeterol: 230/21: 317 pg*h/mL, 115/21: 53pg*h/mL, 45/21: 103 pg*h/mL with a spacer ibrutinib 24 2400%  3 300%steady state: 560 mg with MCL: 865 (69%), MZL: 978 (82%); 420 mg withCLL/SLL 708 (71%), WM 707 (72%), cGVHD 1159 (50%) ivabradine 7 700% 2.1210% ivacaftor 3 300% single 150 mg dose: 10600 +/− 5260 ivacaftor/ivacaftor: ivacaftor: AUC0-12 ivacaftor: tezacaftor 2.95; 295%; 11.3 +/−4.6; tezacaftor: tezacaftor AUC0-24 tezacaftor: 2.0 200% 84.5 +/− 27.8ivosidenib 2.69 269% 1.73 173% 500 mg steady state: 117,348 (50)naloxegol 12.85 1285%  3.41 341% AUC0-12 steady state 25 mg: 363.9 +/−151 nilotinib 3 300% AUC0-12, 400 mg bid: 18000 (33); 300 mg bid: 13337(46) olaparib 2.2 220% AUC steady state: 300 mg tablets, 49 ug*h/mL; 400mg capsules bid, 43.5 ug*h/mL palbociclib 1.87 187% AUC0-10: 125 mg, 724(38) panobinostat 1.73 173% pazopanib 1.7 170% 1037 ug*h/mL regorafenib1.33 133% steady state: 58.3 ug*h/mL ribociclib 3.2 320% AUC0-6 after 8days at 600 mg: 11173 +/− 1830 rivaroxaban 1.76 176% 1.52 152% AUC aftera single dose: 2.5 mg, 321 (28.8); 10 mg fed, 1201 (21.3); 15 mg fed,1801 (22.2); 20 mg fed, 2294 (19.0) ruxolitinib 1.91 191% ranged from862 to 30700 nM*h over a dose range of 5 to 200 mg sonidegib 2.2 220%steady state AUC0-24: 22 ug/mL sunitinib 1.51 151% single dose AUC0-inf:1063 +/− 262 tofacitinib 1.75 175% AUC0-24, ss: 5 mg bid rheumatoidarthritis: 504 (22); 5 mg bid psoriatic arthritis: 419 (34); 5 mg bidulcerative colitis: 423 (23), 10 mg bid ulcerative colitis: 807 (25)vemurafenib AUC0-12 steady state 960 mg bid: 601 +/− 70 ug*h/mLvenetoclax 1.78 178% AUC0-24 400 mg: 32.8 +/− 16.9 ug/mL Cmaxco-administration levels Cmax target safe level Baseline Cmax (% CV)Percent of Percent of (ng/mL unless CYP3A4 drug Fold change baselineFold change baseline otherwise specified) abemaciclib 150 mg Q12H: 249,200 mg Q12H: 298 apalutamide 1.38 138% 6.0 +/− 1.7 ug/mL aripiprazole1.4 140% 3 mg steady state: 44.3 +/− 29.3 bosutinib 1.5 150% multiple400 mg doses: 146 +/− 20; multiple 500 mg doses: 200 +/− 12brexpiprazole 1.2 120% 1 mg: 12.1 +/− 3.79; 2 mg: 24.6 +/− 5.58; 4 mg:47.3 +/− 16.4 brigatinib 1.21 121% steady state 90 mg: 552 (65); 180 mg1452 (60) cabazitaxel 25 mg/m2 q3w: 226 (107) cariprazine 3.5 350% 3 mgsteady state: 10.2 +/− 4.69; 6 mg steady state: 22.7 +/− 4.18cobimetinib 3.2 320% 273 (60) copanlisib 1.03 103% 463 +/− 584crizotinib 1.33 133% steady state at 250 mg BID: 411 (44) dabrafenib day15 150 mg BID: 806 (95.1) daclatasvir 1.57 157% steady state 60 mg: 182+/− 137 dapagliflozin/ saxagliptin: saxagliptin: saxagliptin: 24saxagliptin 2.44 244% deflazacort single dose 30 mg: 116 duvelisib 1.7170% steady state 25 mg bid: 1.5 (64) ug/mL elbasvir/ EBR: 1.29; EBR:129%; EBR: 121; grazoprevir GZR: 1.13 GBR: 113% GZR: 165 encorafenib1.45 145% median, 450 mg steady state: 3800 (range 2870-7000)flibanserin 1.1 110% single 100 mg dose: 419 +/− 206 fluticasonesalmeterol: salmeterol: steady state fluticasone propionate/ 1.4 140%45/21: 41 pg/mL, salmeterol 115/21: 108 pg/mL, xinafoate 230/21: 173pg/mL; salmeterol: ranged from 220-470 pg/mL across dose range ibrutinib29 2900%  3.4 340% ivabradine 3.25 325% 1.6 160% ivacaftor 2.7 270%single 150 mg dose: 768 +/− 233 ivacaftor/ ivacaftor: ivacaftor:ivacaftor: tezacaftor 2.47; 247%; 1.17 +/− 0.424 ug/mL; tezacaftor:tezacaftor: tezacaftor: not given not given 5.95 +/− 1.5 ug/mLivosidenib 1.52 152% 500 mg steady state: 6551 (44) naloxegol 9.58 958%2.86 286% steady state 25 mg: 96.87 +/− 55.38 nilotinib 400 mg bid: 2260(35); 300 mg bid: 1540 (48) olaparib 1.1 110% steady state: 300 mgtablets, 7.7 ug/mL; 400 mg capsules bid, 6.18 ug/mL palbociclib 1.34134% 125 mg, 86 (34) panobinostat 1.62 162% 20 mg: 21.6 ng/mL pazopanib1.5 150% 58.1 ug/mL regorafenib steady state: 3.9 ug/mL ribociclib 1.7170% after 11 days at 600 mg: 2610 +/− 547 rivaroxaban 1.56 156%  0%After a single dose: 2.5 mg, 52.0 (28.1); 10 mg fed, 161.7 (17.2); 15 mgfed, 234.2 (17.4); 20 mg fed, 294.4 (15.0) ruxolitinib 1.33 133% rangedfrom 205 to 7100 nM over a dose range of 5 to 200 mg sonidegib 1.5 150% 0% steady state: 1030 sunitinib 1.49 149% single dose: 24.4 +/− 4tofacitinib 1.1 110% vemurafenib steady state 960 mg bid: 61 +/− 17ug/mL venetoclax 1.06 106% 400 mg: 2.1 +/− 1.1 ug/mL

The values in Table A are approximations. In some embodiments, thepercent baseline for the AUC and Cmax target safe levels can vary byabout +25% (e.g., about 1%, about 2%, about 3%, about 4%, about 5%,about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%,about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about19%, about 20%, about 21%, about 22%, about 23%, about 24% or about 25%,inclusive of all ranges therebetween). For example, when the target safelevel in Table A is 130%, the AUC or Cmax level achieved may be 155% or105%. Similarly, in some embodiments, the GMR of AUC or Cmax may vary byabout ±25%.

Because the potentially adverse consequences of leaving a patientuntreated with the CYP3A4 substrate drug must be balanced with potentialrisks associated with effects of a DDI between the CYP3A4 substrate drugand posaconazole (e.g., elevation of plasma levels and elevated exposureto the CYP3A4 substrate drug), a person of skill in the art (e.g., aphysician) would administer a dose of the CYP3A4 substrate drug as soonas it would be safe to do so. For example, a physician would dose theCYP3A4 substrate drug as soon as doing so would not result in clinicallysignificant, elevated plasma levels or exposure to the CYP3A4 drug thatexceed the target levels considered safe. Such a physician would notwait for a longer period of time, as even though lower plasma levels ofposaconazole would reduce the potentially adverse effects of a DDI, thepatient would not receive the benefit of being treated with the CYP3A4substrate drug (or alternatively, be exposed to risks associated withremaining untreated). For certain CYP3A4 substrate drugs, the CYP3A4substrate drug is contraindicated for coadministration withposaconazole. A person of skill in the art would therefore construe sucha contraindication to mean that only coadministration of the CYP3A4substrate drug with the CYP3A4 inhibitor (e.g., posaconazole) is unsafe;but it would be safe to administer 100% of the reference dose (asdefined herein) of the CYP3A4 substrate drug as soon as the day afterthe last dose of posaconazole (i.e., the day after “stopping”posaconazole).

However, Applicant discovered that the inhibitory effects ofposaconazole on CYP3A4 last substantially longer than would have beenpredicted from its half-life. Applicant also discovered thatposaconazole levels remain higher than expected for a longer period oftime, obese patients as defined herein). See FIG. 8, which shows thatthe actual lurasidone AUC levels (dashed lines) measured in a patientafter stopping posaconazole are unexpectedly higher after stoppingposaconazole than predicted in the prior art by posaconazole half-life(solid line); see also FIG. 9 which also shows that actual ranolazineAUC levels (dashed lines) are significantly higher the predicted AUClevels (solid line). This previously unknown persistence of posaconazoleinhibition of CYP3A4 poses an increased risk of causing serious sideeffects upon subsequent administration of CYP3A4 substrate drugs, whichwas not previously appreciated. To mitigate this risk, in someembodiments the administration of the CYP3A4 substrate drug iscontraindicated not just for coadministration with posaconazole, but theadministration is also contraindicated for a period of time (e.g., 2 ormore days) after stopping posaconazole beyond the label-prescribed delayof one day (i.e., contraindication for coadministration of the CYP3A4substrate drug and posaconazole). In some embodiments, the presentmethods provide for administering the CYP3A4 substrate drug as soon asit is safe to do so, e.g., for time periods exceeding about 1 day, asdescribed herein. Administering the CYP3A4 substrate drug “as soon as itis safe” does not mean waiting until all or almost all of theposaconazole is eliminated from the patient in order to minimize theDDI. Rather, administering the CYP3A4 substrate drug “as soon as it issafe” generally means administering the CYP3A4 substrate drug even whenposaconazole plasma levels are such that an appreciable DDI effect isstill present. The CYP3A4 substrate drug is administered as soon as theeffects of the DDI are low enough such that the blood plasma levels ofthe CYP3A4 substrate drug do not exceed target safe levels. Thisaccounts for the need to treat the patient with the CYP3A4 substratedrug with no more delay (after stopping posaconazole) than is necessary,so that the risks of leaving such a patient untreated are minimized asmuch as possible.

As used herein, “safe”, such as usages in which the CYP3A4 substratedrug is administered “as soon as it is safe” and “safe level”, means assoon as inhibition of CYP3A4 by posaconazole would not present anunacceptable risk of serious side effects to the patient (e.g., due toblood plasma levels of the CYP3A4 substrate drug). An “unacceptable riskof serious side effects” occurs e.g., when risks associated withelevated exposure to the CYP3A4 substrate drug are, on balance, greaterthan the risk of not treating the patient with the CYP3A4 substratedrug. In some embodiments, and as unexpectedly discovered by theApplicant, administering the CYP3A4 substrate drug “as soon as it issafe” requires waiting longer than would have been predicted by theprior art—i.e., waiting longer than 1 day after stopping posaconazolebased on the label contraindication of coadministration of the CYP3A4substrate drug and posaconazole. By implication, “unsafe” as used hereinmeans when risks associated with treating a patient (e.g., elevatedexposure to the CYP3A4 substrate drug) are greater than the risk of nottreating the patient. Thus, the present methods account for thepreviously unknown magnitude and the unknown duration of the inhibitoryeffects of posaconazole on CYP3A4, as well as the need to treat thepatient with the CYP3A4 substrate drug.

In some embodiments, the CYP3A4 substrate drug is administered as soonas treatment would provide a favorable risk/benefit profile. Therisk/benefit profile weights the patient's risk(s) of potential adverseevent(s) if treated compared to the benefit(s) of treatment.Non-limiting examples of factors used to assess the risk/benefit profileinclude: (i) the type of benefit(s) the patient would receive (e.g.,treatment end points and the value of treatment to the patient); (ii)magnitude of the benefit(s); (iii) probability of the patientexperiencing one or more benefit(s); (iv) duration of effect(s) andwhether to duration is a benefit; (v) severity, types, number, and ratesof harmful events (e.g., serious vs. non-serious adverse events); (vi)probability of a harmful event (e.g., the percentage of the patientpopulation that would be expected to experience a harmful event; theincidence of each harmful event in the study population; degree ofuncertainty in determination probability; patient's willingness toaccept the probable risk of the harmful event, given the probablebenefit); (vii) duration of harmful events (e.g., how long does theharmful event last and is it reversible; types of intervention requiredto address the harmful event); (viii) medical necessity (e.g., does theCYP3A4 substrate drug provide a benefit or address a need unmet by othertherapies). In the context of a potential drug-drug interaction betweena CYP3A4 inhibitor such as posaconazole and a CYP3A4 substrate drug(including those disclosed herein) appropriate dosing of the CYP3A4substrate drug in the presence of a CYP3A4 inhibitor requires balancingthe various risk and benefit factors (e.g., as described above). Theappropriate dosing for a CYP3A4 substrate drug, resulting from anevaluation of the risk/benefit profile is conventionally incorporatedinto the FDA-approved drug label. To be clear, an elevation in PK (e.g.,Cmax, AUC, or GMR of AUC or Cmax) is not the only factor that a personof skill in the art (e.g., a physician) would consider to be relevant indeciding whether to administer a CYP3A4 substrate drug. In someembodiments, the patient is administered the CYP3A4 substrate drug assoon as the benefit(s) outweigh the risk(s). In some embodiments, thepatient is administered the full reference dose as soon as thebenefit(s) outweigh the risk(s). In some embodiments, the patient isadministered a reduced dose as soon as the benefit(s) outweigh therisk(s).

In some embodiments, the CYP3A4 substrate drug is administered as soonas least one or more of the Cmax, AUC, and GMR of AUC or Cmax of theCYP3A4 substrate drug, after such administration, would be at a safelevel. In some embodiments, the safe levels are less than thecoadministration Cmax, AUC, and/or GMR levels provided for CYP3A4substrate drugs in Table A, e.g., about 5%, about 10%, about 15%, about20%, about 25%, about 30%, about 25%, about 40%, about 45%, about 50%,about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about85%, about 90%, or about 95% less than coadministration levels. In someembodiments, the CYP3A4 substrate drug is administered as soon as a timewhen one or more of the Cmax, AUC, average AUC, and GMR of AUC or Cmaxof the CYP3A4 substrate drug is elevated to levels that would not havebeen predicted (e.g., higher than would have been predicted), and indeedwould have been considered highly improbable, based on the prior art'sunderstanding of the CYP3A4 inhibitor's (e.g., posaconazole's) impact onsuch levels for the CYP3A4 substrate drugs. In some embodiments, theCYP3A4 substrate drug can be safely administered as soon as the Cmax orAUC of the CYP3A4 substrate drug is about 3000%, about 2900%, about2800%, about 2700%, about 2600%, about 2500%, about 2400%, about 2300%,about 2200%, about 2100%, about 2000%, about 1900%, about 1800%, about1700%, about 1600%, about 1500, about 1400%, about 1300%, about 1200%,about 1100%, about 1000%, about 990%, about 980%, about 970%, about960%, about 950%, about 940%, about 930%, about 920%, about 910%, about900%, about 890%, about 880%, about 870%, about 860%, about 850%, about840%, about 830%, about 820%, about 810%, about 800%, about 790%, about780%, about 770%, about 760%, about 750%, about 740%, about 730%, about720% out 710%, about 700%, about 690%, about 680%, about 670%, about660%, about 650%, about 640%, about 630%, about 620%, about 610%, about600%, about 590% about 560%, about 550%, about 540%, about 530%, about520%, about 510%, about 500%, about 490%, about 480%, about 470%, about460%, about 450%, about 440%, about 430%, about 420%, about 410%, about400%, about 390%, about 380%, about 370%, about 360%, about 350%, about340%, about 330%, about 320%, about 310%, about 300%, about 290%, about280%, about 270%, about 260%, about 250%, about 240%, about 230%, about220%, about 210%, about 200%, about 190%, about 180%, about 170%, about160%, about 150%, about 140%, about 130%, about 120%, about 110%, andabout 105% of the respective normal baseline values of such parameters(Table A) after stopping posaconazole (inclusive of all ranges inbetween). In some embodiments, the CYP3A4 substrate drug can be safelyadministered as soon as 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33,34, 35, 36, 37, 38, 39, 40, 41, or 42 days after stopping posaconazole,inclusive of ranges in between. In some embodiments, the CYP3A4substrate drug can be safely administered as soon as the GMR of AUC orCmax of the CYP3A4 substrate drug is about 30 fold, about 29 fold, about28 fold, about 27 fold, about 26 fold, about 25 fold, about 24 fold,about 23 fold, about 22 fold, about 21 fold, about 20 fold, about 19fold, about 18 fold, about 17 fold, about 16 fold, about 15 fold, about14 fold, about 13 fold, about 12 fold, about 11 fold, about 10 fold,about 9.9 fold, about 9.8 fold, about 9.7 fold, about 9.6 fold, about9.5 fold, about 9.4 fold, about 9.3 fold, about 9.2 fold, about 9.1fold, about 9 fold, about 8.9 fold, about 8.8 fold, about 8.7 fold,about 8.6 fold, about 8.5 fold, about 8.4 fold, about 8.3 fold, about8.2 fold, about 8.1 fold, about 8.0 fold, about 7.9 fold, about 7.8fold, about 7.7 fold, about 7.6 fold, about 7.5 fold, about 7.4 fold,about 7.3 fold, about 7.2 fold, about 7.1 fold, about 7.0 fold, about6.9 fold, about 6.8 fold, about 6.7 fold, about 6.6 fold, about 6.5fold, about 6.4 fold, about 6.3 fold, about 6.2 fold, about 6.1 fold,about 6.0 fold, about 5.9 fold, about 5.8 fold, about 5.7 fold, about5.6 fold, about 5.5 fold, about 5.4 fold, about 5.3 fold, about 5.2fold, about 5.1 fold, about 5.0 fold, about 4.9 fold, about 4.8 fold,about 4.7 fold, about 4.6 fold, about 4.5 fold, about 4.4 fold, about4.3 fold, about 4.2 fold, about 4.1 fold, about 4.0 fold, about 3.9fold, about 3.8 fold, about 3.7 fold, about 3.6 fold, about 3.5 fold,about 3.4 fold, about 3.3 fold, about 3.2 fold, about 3.1 fold, about3.0 fold, about 2.9 fold, about 2.8 fold, about 2.7 fold, about 2.6fold, about 2.5 fold, about 2.4 fold, about 2.3 fold, about 2.2 fold,about 2.1 fold, about 2.0 fold, about 1.9 fold, about 1.8 fold, about1.7 fold, about 1.6 fold, about 1.5 fold, about 1.4 fold, about 1.3fold, about 1.2 fold, about 1.1 fold, and about 1.05 fold compared tothe respective normal baseline values of such parameters, after stoppingposaconazole (inclusive of all ranges in between). In some embodiments,the CYP3A4 substrate drug can be safely administered as soon as 2, 3, 4,5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23,24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41,or 42 days after stopping posaconazole, inclusive of all values andsubranges therebetween. In some embodiments, the patient is administeredthe full reference dose of the CYP3A4 substrate drug to achieve any ofthe above Cmax or AUC values, or any of the above fold changes in GMR ofCmax or AUC. In some embodiments, after stopping posaconazole, thepatient is administered a reduced dose of the CYP3A4 substrate drug toachieve any of the above Cmax or AUC values, or fold changes in GMR ofCmax or AUC.

In some embodiments, the methods disclosed herein provide foradministering a dose of CYP3A4 substrate to achieve one or more PKparameters (AUC, Cmax, and GMR of AUC or Cmax) that are above therespective values predicted for that dose of the CYP3A4 substrate drug,based on the conventionally understood posaconazole half-life of 27 hrs.(patients with normal hepatic function), 39 hrs. (patients with mildhepatic impairment), 27 hrs. (patients with moderate hepaticimpairment), and 43 hrs. (patients with severe hepatic impairment),about 24 hours after dosing with posaconazole injection, about 31 hoursafter administration of posaconazole delayed-release tablets, and about31-37 hours after administration of posaconazole oral suspension.Noxafil® label, revised 09/2016. FIG. 8 depicts the actual lurasidoneAUC levels (as a multiple of baseline AUC; dashed lines) resulting fromadministration of 100% of the reference dose in normal weight and obesepatients at various times after stopping posaconazole as measured inApplicant's research compared to the lurasidone levels predicted fromposaconazole's half-life as described in the Noxafil® label (“predictedlevels”; solid line) using equation 1 and a posaconazole half-life of 31hours. The solid line shows that predicted lurasidone AUC levels(reported as GMR) are about 400% (or about 4 fold) greater than baseline1 day after stopping posaconazole, about 300% (or about 3 fold) greaterthan baseline 2 days after stopping posaconazole, about 200% (or about 2fold) greater than baseline about 3 days after stopping posaconazole,and then tapering off to reach baseline around day 9 after stoppingposaconazole. In contrast, Applicant's data shows that actual lurasidoneAUC levels are significantly above predicted levels for at least 14 daysafter stopping posaconazole, e.g., about 2 fold greater than expected 2days after stopping posaconazole; about 2-3 fold greater than expected 3days after stopping posaconazole; about 2.5-3.5 fold greater thanexpected 4 days after stopping posaconazole, and remain about 2-3 foldabove expected levels for at least about 14 days. The same studies wereperformed with ranolazine. Like FIG. 8, FIG. 9 depicts the actualranolazine AUC levels (as a multiple of baseline AUC; dashed lines) fornormal weight and obese patients resulting from administration of 100%of the reference dose at various times after stopping posaconazole asmeasured in Applicant's research, compared to the ranolazine levelspredicted from posaconazole's half-life of 31 hours as described in theNoxafil® label (“predicted levels”; solid line). Applicant's data showsthat the actual ranolazine AUC levels are significantly above predictedlevels for at least 14 days after stopping posaconazole, e.g., about0.5-1.5 fold greater than expected 2 days after stopping posaconazole;about 1.5 fold greater than expected 3 days after stopping posaconazole;about 1.5 fold greater than expected 4 days after stopping posaconazole,and remaining about 0.5-1.5 fold above expected levels for at leastabout 14 days. In some embodiments, the present methods administer aCYP3A4 substrate drug (e.g., lurasidone, ranolazine, or any other CYP3A4substrate drug, such as those described herein) to achieve blood plasmalevels above the expected levels measured for the reference dose.

In some embodiments, the present methods provide for administeringlurasidone on a specified day after stopping posaconazole when at leastone of the AUC, Cmax, and/or GMR of AUC or Cmax of lurasidone is abovethe predicted levels (e.g., the DDI decay curve calculated usingequation 1 and the accepted half-life of posaconazole) on the specifiedday as depicted in FIG. 8. In some embodiments, lurasidone isadministered when at least one of the AUC or Cmax of lurasidone areabout 105%, about 110%, about 115%, about 120%, about 125%, about 130%,about 135%, about 140%, about 145%, about 150%, about 155%, about 160%,about 165%, about 170%, about 175%, about 180%, about 185%, about 190%,about 195%, about 200%, about 210%, about 215%, about 216%, about 220%,about 225%, about 230%, about 235%, about 240%, about 245%, about 250%,about 255%, about 260%, about 265%, about 270%, about 275%, about 280%,about 285% about 290%, about 295%, about 300%, about 305%, about 310%,about 315%, about 320%, about 325%, about 330%, about 335%, about 340%,about 345%, about 350%, about 355%, about 360%, about 365%, about 370%,about 375%, about 380%, about 385%, about 390%, about 395%, or about400% of baseline levels, inclusive of all values and rangestherebetween. In some embodiments, the CYP3A4 substrate drug isadministered when at least one of the GMR of AUC or Cmax of lurasidoneare increased by about 1.05 fold, about 1.1 fold, about 1.15 fold, about1.2 fold, about 1.25 fold, about 1.3 fold, about 1.35 fold, about 1.4fold, about 1.45 fold, about 1.50 fold, about 1.55 fold, about 1.60fold, about 1.65 fold, about 1.7 fold, about 1.75 fold, about 1.8 fold,about 1.85 fold, about 1.9 fold, about 1.95 fold, about 2.0 fold, about2.1 fold, about 2.15 fold, about 2.16 fold, about 2.2 fold, about 2.24fold, about 2.25 fold, about 2.3 fold, about 2.35 fold, about 2.40 fold,about 2.45 fold, about 2.50 fold, about 2.55 fold, about 2.60 fold,about 2.65 fold, about 2.7 fold, about 2.75 fold, about 2.8 fold, about2.85 fold, about 2.9 fold, about 2.95 fold, about 3.0 fold, about 3.05fold, about 3.1 fold, about 3.15 fold, about 3.20 fold, about 3.25 fold,about 3.30 fold, about 3.35 fold, about 3.40 fold, about 3.45 fold,about 3.50 fold, about 3.55 fold, about 3.60 fold, about 3.65 fold,about 3.7 fold, about 3.75 fold, about 3.8 fold, about 3.85 fold, about3.9 fold, about 3.95 fold, or about 4.0 fold, inclusive of all valuesand ranges therebetween. In some embodiments, lurasidone administration(e.g., 100% of the reference dose or a reduced dose) begins as soon as2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21,22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39,40, 41, or 42 days (inclusive of all values and subranges therebetween)after stopping posaconazole.

In some embodiments, the present methods provide for administeringranolazine on a specified day after stopping posaconazole when at leastone of the AUC, Cmax, and/or GMR of AUC or Cmax of ranolazine is abovethe predicted levels (e.g., the DDI decay curve calculated usingequation 1 and the accepted half-life of posaconazole) on the specifiedday as depicted in FIG. 9. In some embodiments, ranolazine isadministered when at least one of the AUC or Cmax of ranolazine areabout 105%, about 110%, about 115%, about 120%, about 125%, about 130%,about 135%, about 140%, about 145%, or about 150% of baseline levels,inclusive of all values and ranges therebetween. In some embodiments,ranolazine is administered when at least one of the GMR of AUC or Cmaxof ranolazine are increased by about 1.05 fold, about 1.1 fold, about1.15 fold, about 1.2 fold, about 1.25 fold, about 1.3 fold, about 1.35fold, about 1.4 fold, about 1.45 fold, or about 1.50 fold. In someembodiments, ranolazine administration (e.g., 100% of the reference doseor a reduced dose) begins as soon as 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30,31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, or 42 days (inclusive of allvalues and subranges therebetween) after stopping posaconazole.

Applicant's observations from its clinical research with lurasidone andranolazine indicates that dosing of other CYP3A4 substrate drugs shouldoccur at least two days (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31,32, 33, 34, 35, 36, 37, 38, 39, 40, 41, or 42 days) after stoppingposaconazole. In some embodiments, Applicant discovered the CYP3A4substrate drug can be administered after stopping posaconazole when oneor more of the Cmax, AUC, and/or GMR of AUC or Cmax of the CYP3A4substrate drug is elevated to levels that would not have been predicted(e.g., the DDI decay curve calculated using equation 1 and the acceptedhalf-life of posaconazole), and indeed would have been considered highlyimprobable at a particular day after stopping posaconazole therapy.Because certain blood plasma levels may be unsafe, in some embodiments,the present methods provide for administering a CYP3A4 substrate drugwhen (e.g., as soon as) the at least one of the AUC, Cmax, or GMR of AUCor Cmax of the CYP3A4 substrate drug is at or below a maximum level, butabove the predicted levels. In some embodiments, the maximum level is ablood plasma level of the CYP3A4 substrate drug when the benefits oftreating the patient with the CYP3A4 substrate drug outweigh the risks.Above the maximum level, the risks of treatment outweigh the benefits.Non-limiting examples of maximum levels for various CYP3A4 substratedrugs are provided in Table A indicated as “target safe levels”. In someembodiments, the CYP3A4 substrate drug is administered when at least oneof the actual AUC or Cmax of the CYP3A4 substrate drug ranges from about3000% to about 105% of the expected the AUC or Cmax, e.g., about 3000%,about 2900%, about 2800%, about 2700%, about 2600%, about 2500%, about2400%, about 2300%, about 2200%, about 2100%, about 2000%, about 1900%,about 1800%, about 1700%, about 1600%, about 1500, about 1400%, about1300%, about 1200%, about 1100%, about 1000%, about 950%, about 900%,about 850%, about 800%, about 750%, about 700%, about 650%, about 600%,about 550%, about 500%, about 450%, about 400%, about 350%, about 300%,about 250%, about 200%, about 195%, about 190%, about 185%, about 180%,about 175%, about 170%, about 165%, about 160%, about 155%, about 150%,about 145%, about 140%, about 135%, about 130%, about 125%, about 120%,about 115%, about 110%, and about 105%, and any ranges in between thesevalues. In some embodiments, the CYP3A4 substrate drug is administeredwhen at least one of the GMR of AUC or Cmax of the CYP3A4 substrate drugranges from about 30 fold to about 1.05 fold of the baseline AUC orCmax, e.g., about 30 fold, about 29 fold, about 28 fold, about 27 fold,about 26 fold, about 25 fold, about 24 fold, about 23 fold, about 22fold, about 21 fold, about 20 fold, about 19 fold, about 18 fold, about17 fold, about 16 fold, about 15 fold, about 14 fold, about 13 fold,about 12 fold, about 11 fold, about 10 fold, about 9.9 fold, about 9.8fold, about 9.7 fold, about 9.6 fold, about 9.5 fold, about 9.4 fold,about 9.3 fold, about 9.2 fold, about 9.1 fold, about 9 fold, about 8.9fold, about 8.8 fold, about 8.7 fold, about 8.6 fold, about 8.5 fold,about 8.4 fold, about 8.3 fold, about 8.2 fold, about 8.1 fold, about8.0 fold, about 7.9 fold, about 7.8 fold, about 7.7 fold, about 7.6fold, about 7.5 fold, about 7.4 fold, about 7.3 fold, about 7.2 fold,about 7.1 fold, about 7.0 fold, about 6.9 fold, about 6.8 fold, about6.7 fold, about 6.6 fold, about 6.5 fold, about 6.4 fold, about 6.3fold, about 6.2 fold, about 6.1 fold, about 6.0 fold, about 5.9 fold,about 5.8 fold, about 5.7 fold, about 5.6 fold, about 5.5 fold, about5.4 fold, about 5.3 fold, about 5.2 fold, about 5.1 fold, about 5.0fold, about 4.9 fold, about 4.8 fold, about 4.7 fold, about 4.6 fold,about 4.5 fold, about 4.4 fold, about 4.3 fold, about 4.2 fold, about4.1 fold, about 4.0 fold, about 3.9 fold, about 3.8 fold, about 3.7fold, about 3.6 fold, about 3.5 fold, about 3.4 fold, about 3.3 fold,about 3.2 fold, about 3.1 fold, about 3.0 fold, about 2.9 fold, about2.8 fold, about 2.7 fold, about 2.6 fold, about 2.5 fold, about 2.4fold, about 2.3 fold, about 2.2 fold, about 2.1 fold, about 2.0 fold,about 1.9 fold, about 1.8 fold, about 1.7 fold, about 1.6 fold, about1.5 fold, about 1.4 fold, about 1.3 fold, about 1.2 fold, about 1.1fold, and about 1.05 fold compared to the respective normal baselinevalues of such parameters, after stopping posaconazole (inclusive of allranges in between). In some embodiments, administration begins 2, 3, 4,5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23,24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41,or 42 days (inclusive of all values and subranges therebetween) afterstopping posaconazole. For example, in some embodiments, lurasidone isadministered such that the AUC is between about 400% and 105%, betweenabout 300% and about 105%, or between about 216% and 105% of the normalbaseline, and this could occur on 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23,24, 25, 26, 27, 28, 29, 30,31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, or 42 days after stoppingposaconazole. As another example, some embodiments administer ranolazineto provide an AUC between about 150% and 105% of the normal baseline,and this could occur on 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33,34, 35, 36, 37, 38, 39, 40, 41, or 42 days after stopping posaconazole.

In some embodiments, the present methods require that the CYP3A4substrate drug is not dosed when blood plasma levels of the substratedrug (i.e., at least one of AUC, Cmax, or GMR of AUC or Cmax) wouldotherwise exceed a specified maximum level (e.g., by about 25%) if saidsubstrate drug were administered. That is, in some embodiments, themaximum level determines when to administer the CYP3A4 substratedrug—the CYP3A4 substrate drug is administered only when at least one ofan AUC, Cmax, or GMR of AUC or Cmax would be at or below the maximumlevel. In some embodiments, the maximum level is less than at least oneof the AUC, Cmax, or GMR of AUC or Cmax of the CYP3A4 substrate drugthat would occur if said substrate drug was coadministered withposaconazole (See AUC and Cmax co-administration levels in Table A). Insome embodiments, the maximum level is a blood plasma level at which thebenefits of treating the patient with the CYP3A4 substrate drug outweighthe risks. In some embodiments, the maximum level is a target safe levelprovided in Table A. When administering the CYP3A4 substrate drug wouldcause at least one of the AUC, Cmax, or GMR of AUC or Cmax levels toexceed the target safe level, administration is delayed until at leastone of the AUC, Cmax, or GMR of AUC or Cmax levels are at or below thetarget safe level.

In some embodiments, the maximum level is related to the incidence of anadverse event. In some embodiments, the incidence rate of the adverseevent which establishes the maximum level is at least about 2%, at leastabout 5%, at least about 10%, at least about 15%, at least about 20%, atleast about 25%, at least about 30%, at least about 35%, at least about40%, at least about 45%, at least about 50% in a population of patientsreceiving the same treatments. In some embodiments, the determination ofwhether to dose the CYP3A4 substrate drug is based on a risk/benefitanalysis (e.g., as discussed above).

Using lurasidone as an example, an increase of about 300% in the AUC oflurasidone (about 3 fold increase in GMR) is associated with somnolence,whereas an increase of 400% in AUC (or about 4 fold increase in GMR) isassociated with akathisia. Because of the benefit of treating a patient,in some embodiments, lurasidone is administered when the AUC isincreased by up to about 300% (about a 3 fold increase in GMR), but notwhen the AUC would be increased by about 400% (about a 4 fold increasein GMR). In some embodiments, the maximum level for lurasidone is a 216%increase in baseline AUC. In some embodiments, e.g., when the patient'sneed for treatment outweighs the risks, the maximum level may be about500% increase in baseline AUC. In other embodiments, the maximum levelmay be any value in the range of less than 500% to 216% increase inbaseline AUC, including any ranges in between those values. Accordingly,in some embodiments, the maximum level for lurasidone is 400%, about300%, or about 216% of the normal baseline level of AUC. Thus, in someembodiments, lurasidone is administered as soon as the AUC is less thanor equal to about 400%, about 350%, about 300%, about 275%, about 250%,about 225%, about 216%, about 215%, about 210%, about 205%, about 200%,about 195%, about 190%, about 185%, about 180%, about 175%, about 170%,about 165%, about 160%, about 155%, about 150%, about 145%, about 140%,about 135%, about 130%, about 125%, about 120%, about 115%, about 110%,about 105%, inclusive of all values and ranges therebetween, and thismay occur on 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, and 30 days after stoppingposaconazole.

In some embodiments, the CYP3A4 substrate drug is not dosed when atleast one of the AUC or Cmax would be greater than about 3000% of anormal baseline AUC (as defined above) of the CYP3A4 substrate drug,e.g., greater than about 2900%, greater than about 2800%, greater thanabout 2700%, greater than about 2600%, greater than about 2500%, greaterthan about 2400%, greater than about 2300%, greater than about 2200%,greater than about 2100%, greater than about 2000%, greater than about1900%, greater than about 1800%, greater than about 1700%, greater thanabout 1600%, greater than about 1500%, greater than about 1400%, greaterthan about 1300%, greater than about 1200%, greater than about 1100%,greater than about 1000%, greater than about 950%, greater than about900%, greater than about 850%, greater than about 800%, greater thanabout 750%, greater than about 700%, greater than about 650%, greaterthan about 600%, greater than about 550%, greater than about 500%,greater than about 450%, greater than about 400%, greater than about350%, greater than about 300%, greater than about 250%, greater thanabout 200%, greater than about 190%, greater than about 180%, about170%, greater than about 160%, greater than about 150%, greater thanabout 145%, greater than about 140%, greater than about 135%, greaterthan about 130%, greater than about 125%, greater than about 120%,greater than about 115%, or greater than about 110%, inclusive of allvalues and subranges therebetween. In some embodiments, the CYP3A4substrate drug is not dosed when at least one of the GMR of AUC or Cmaxwould be greater than about 30 fold of a normal baseline AUC (as definedabove) of the CYP3A4 substrate drug, e.g., greater than about 30 fold,greater than about 29 fold, greater than about 28 fold, greater thanabout 27 fold, greater than about 26 fold, greater than about 25 fold,greater than about 24 fold, greater than about 23 fold, greater thanabout 22 fold, greater than about 21 fold, greater than about 20 fold,greater than about 19 fold, greater than about 18 fold, greater thanabout 17 fold, greater than about 16 fold, greater than about 15 fold,greater than about 14 fold, greater than about 13 fold, greater thanabout 12 fold, greater than about 11 fold, greater than about 10 fold,greater than about 9.5 fold, greater than about 9 fold, greater thanabout 8.5 fold, greater than about 8.0 fold, greater than about 7.5fold, greater than about 7.0 fold, greater than about 6.5 fold, greaterthan about 6.0 fold, greater than 5.5 fold, greater than about 5.0 fold,greater than about 4.5 fold, greater than about 4.0 fold, greater thanabout 3.5 fold, greater than about 3.0 fold, greater than about 2.5fold, greater than about 2.0 fold, greater than about 1.9 fold, greaterthan about 1.8 fold, greater than about 1.7 fold, greater than about 1.6fold, greater than about 1.5 fold, greater than about 1.4 fold, greaterthan about 1.3 fold, greater than about 1.2 fold, or greater than about1.1 fold, inclusive of all values and subranges therebetween.

As discussed herein, Applicant discovered that the inhibitory effects ofposaconazole on CYP3A4 last substantially longer than would have beenpredicted from its half-life. Accordingly, in some embodiments, thepresent methods provide for administering the CYP3A4 substrate drug assoon as sufficient posaconazole has been eliminated from the patient,such that the drug-drug interaction between posaconazole and the CYP3A4substrate drug (e.g., clinically relevant adverse events associated withelevated levels of the CYP3A4 substrate drug) does not pose anunacceptable risk to the patient. As described in Examples 2 and 3, theelimination half-life of posaconazole is different in normal weight andobese patients, and therefore the delay period required to safely dosethe CYP3A4 substrate drug after stopping posaconazole may be differentin these patient populations. Specifically, Applicant measured theelimination half-life of posaconazole for normal weight patients at 33.6hours, whereas the elimination half-life of posaconazole in obesepatient was measured to be 58.3 hours. Table B shows the meansteady-state concentration of posaconazole measured for normal and obesepatients measured in two separate clinical studies performed byApplicant (BOW-001 and BOW-002). The two clinical studies used the sameprotocol to measure posaconazole's elimination half-life, allowing forthe data for normal patients from each study to be combined (“AllNormal”) and data for obese patients from each study to be combined(“All Obese”).

TABLE B Pooled Posaconazole Elimination Half-Life Data. Css (ng/mL) t½(h) Mean SD Mean SD BOW-001 3071 1422 35.7 11 Normal BOW-002 2514 143530.9 7 Normal BOW-001 2258 952 64.5 53 Obese BOW-002 1462 649 52.5 31Obese All Normal 2864 1400 33.6 9 All Obese 1860 896 58.3 42

In some embodiments, the CYP3A4 substrate drug is dosed after at leastabout 2 half-lives of posaconazole have elapsed, e.g., about 2half-lives, about 3 half-lives, about 4 half-lives, about 5 half-lives,about 6 half-lives, about 7 half-lives, about 8 half-lives, about 9half-lives, about 10 half-lives, about 11 half-lives, about 12half-lives, about 13 half-lives, about 14 half-lives, about 15half-lives, about 16 half-lives, about 17 half-lives, about 18half-lives, about 19 half-lives, about 20 half-lives, about 21half-lives, about 22 half-lives, about 23 half-lives, about 24half-lives, about 25 half-lives, about 26 half-lives, about 27half-lives, about 28 half-lives, about 29 half-lives, or about 30half-lives or more, inclusive of all values and subranges therebetween.

In some embodiments, the timing of administration of the CYP3A4substrate drug is based on posaconazole levels as measured by applicant.In some embodiments, the CYP3A4 substrate drug is administered whenposaconazole levels are reduced by at least about 50% of the steadystate levels, e.g., reduced by about 55%, about 60%, about 65%, about70%, about 75%, about 80%, about 85%, about 87.5%, about 90%, about930.75%, about 95%, about 960.8 75%, about 98.4375%, or about 99%,inclusive of all values and subranges therebetween. In some embodiments,the CYP3A4 substrate drug is administered as soon as posaconazole levelsabout 50% of the steady state levels, e.g., about 45%, about 40%, about35%, about 30%, about 25%, about 20%, about 15%, about 12.5%, about 10%,about 60.25%, about 5%, about 30.125%, about 1.5 625%, or about 1% ofthe steady state levels, inclusive of all values and subrangestherebetween.

In some embodiments, the CYP3A4 substrate drug is administered as soonas two conditions are met: (i) posaconazole levels are reduced by atleast about 50% of the steady state levels (e.g., reduced by about 55%,about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about87.5%, about 90%, about 93.75%, about 95%, about 96.875%, about98.4375%, or about 99%, inclusive of all values and subrangestherebetween); and (ii) the blood plasma levels of the CYP3A4 substratedrug are at or below a target level that is considered safe but abovethe expected levels for the CYP3A4 substrate drug. Expected levels ofthe CYP3A4 substrate drug may be calculated using equation 1. In someembodiments, the target level that is considered safe is the “targetsafe level” disclosed in Table A for the CYP3A4 substrate drug.

In some embodiments, the methods provide for administering a reduceddose (relative to the reference dose, as defined herein) of the CYP3A4substrate drug to the patient. The reduced dose may be administeredconcurrently with posaconazole, the day after stopping posaconazole, orafter any delay period described herein (e.g., 2, 3, 4, 5, 6, 7, 8, 9,10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27,28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, or 42 days afterstopping posaconazole). In some embodiments, the reduced dose isadministered for about 7 to about 42 days, e.g., 7, 8, 9, 10, 11, 12,13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30,31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, or 42 days, inclusive of allvalues and subranges therebetween. In some embodiments, the methodsprovide for selecting a reduced reference dose at that results in amaximum AUC that ranges from about 500% to about 100% (e.g., about 500%,about 475%, about 450%, about 425%, about 400%, about 375%, about 350%,about 325%, about 300%, about 275%, about 250%, about 225%, about 200%,about 175%, about 150%, about 125%, and about 100%, inclusive of allvalues and subranges therebetween) of the normal baseline AUC of thereference dose; and then, on the day that the reduced reference dosewould provide an AUC that is less than 100% of the normal baseline, thepatient is administered the reference dose. In some embodiments, thepatient is administered the reference dose prior to the day that thereduced dose would provide an AUC that is less than 100% of the normalbaseline, provided that when the reference dose is administered, the AUCwould not exceed safe levels as described herein. In some embodiments,the AUC, Cmax, GMR AUC or GMR Cmax provided by administering a reduceddose of the CYP3A4 substrate drug is between the baseline value and atarget safe value listed in Table A for the CYP3A4 substrate drug.

For example, in some embodiments, the methods of the present disclosureprovide for administering a reduced reference dose of lurasidone at thatprovides a maximum GMR that is between about 4.34 and 1 of the patient'snormal baseline; and then, on the day that the reduced reference dosewould provide a GMR that is less than or equal to 1, the patient isadministered the reference dose of lurasidone. In some embodiments, thereference dose of lurasidone may be about 120 mg. In some embodiments,the patient stops taking lurasidone while being treated withposaconazole; then the patient stops treatment with posaconazole andbegins administering a reduced dose of lurasidone (e.g., about 60-80 mg)on any of days 1-3 after stopping posaconazole and for about 21-28 days;on a day ranging from about 21-28 days after stopping posaconazole, thepatient begins administering the 120 mg reference dose of lurasidone.Alternatively, in some embodiments the patient may be administered 60 mgof lurasidone until about 9 days to about 12 days after stoppingposaconazole, and then patient begins administering 120 mg referencedose.

In some embodiments, a reduced dose of the CYP3A4 substrate drug isadministered as soon as posaconazole levels about 50% of the steadystate levels, e.g., about 45%, about 40%, about 35%, about 30%, about25%, about 20%, about 15%, about 12.5%, about 10%, about 60.25%, about5%, about 30.125%, about 1.5 625%, or about 1% of the steady statelevels, inclusive of all values and subranges therebetween.

In some embodiments, a reduced dose of the CYP3A4 substrate drug isadministered as soon as two conditions are met: (i) posaconazole levelsare reduced by at least about 50% of the steady state levels (e.g.,reduced by about 55%, about 60%, about 65%, about 70%, about 75%, about80%, about 85%, about 87.5%, about 90%, about 93.75%, about 95%, about96.875%, about 98.4375%, or about 99%, inclusive of all values andsubranges therebetween); and (ii) the blood plasma levels of the CYP3A4substrate drug are at or below a target level that is considered safebut above the expected levels for the CYP3A4 substrate drug. Expectedlevels of the CYP3A4 substrate drug may be calculated using equation 1.In some embodiments, the target level that is considered safe is the“target safe level” disclosed in Table A for the CYP3A4 substrate drug.

In some embodiments, the CYP3A4 substrate drug is ranolazine. In someembodiments, ranolazine is indicated for chronic angina. In someembodiments, the reference dose to treat chronic angina ranges from500-1000 mg. In some embodiments, the reference dose is adminsteredtwice daily. In embodiments in which the CYP3A4 substrate drug isranolazine, the daily dose of ranolazine is no more than about 500 mg,e.g., about 490 mg, about 480 mg, about 470 mg, about 460 mg, about 450mg, about 440 mg, about 430 mg, about 420 mg, about 410 mg, about 400mg, about 390 mg, about 380 mg, about 370 mg, 360 mg, about 350 mg,about 340 mg, about 330 mg, about 320 mg, about 310 mg, about 300 mg,about 290 mg, about 280 mg, about 270 mg, 260 mg, about 250 mg, about240 mg, about 230 mg, about 220 mg, about 210 mg, about 100 mg, about190 mg, about 180 mg, about 170 mg, 160 mg, about 150 mg, about 140 mg,about 130 mg, about 120 mg, about 110 mg, about 100 mg, about 90 mg,about 80 mg, about 70 mg, about 60 mg, or about 50 mg, inclusive of allvalues and ranges therebetween, and treatment is delayed for at leastabout 2-42 days after discontinuation of the posaconazole regimen, orreduced for the time period of about 2-42 days after discontinuation ofthe posaconazole regimen.

In embodiments, the CYP3A4 substrate drug is lurasidone. In someembodiments, lurasidone is indicated for the treatment of schizophreniain adults and adolescents (13 to 17 years), depressive episodesassociated with Bipolar I Disorder (bipolar depression) in adults,monotherapy or adjunctive therapy with lithium or valproate, moderatebipolar depression, severe bipolar depression, severe bipolar depressionwith acute suicidal ideation and behavior (ASIB). In some embodiments,reference dose for treating schizophrenia in adults ranges from 40-160mg per day (e.g., 40, 60, 80, 100, 120, 140, 160, or 180 mg). In some,the reference dose for treating schizophrenia in adolescents (13-17years) ranges from 48-80 mg (e.g., 40, 60, or 80 mg). In someembodiments, the reference dose for treating bipolar depression inadults ranges from 20-120 mg (e.g., 20, 40, 60, 80, 100, or 120 mg). Insome embodiments, the reference dose for treating bipolar depression inpediatric patients (10-17 years) ranges from 20-80 mg (e.g., 20, 40, 60,or 80 mg). In embodiments in which the CYP3A4 substrate drug islurasidone, the daily dose of lurasidone is no more than about 80 mg,e.g., about 75, about 70 mg, about 65 mg, about 60 mg, about 55 mg,about 50 mg, about 45 mg, about 40 mg, about 35 mg, about 30 mg, about25 mg, about 20 mg, about 15 mg, or about 10 mg, inclusive of all valuesand ranges therebetween, and treatment is delayed for at least about2-42 days after discontinuation of the posaconazole regimen, or reducedfor the time period of about 2-42 days after discontinuation of theposaconazole regimen.

In embodiments in which the CYP3A4 substrate drug is tadalafil, thedaily dose of tadalafil is no more than about 2.5 mg, e.g., about 2.25mg, about 2.0 mg, about 1.75 mg, about 1.5 mg, about 1.25 mg, about 1.0mg, about 0.75 mg, or about 0.5 mg, inclusive of all values and rangestherebetween, and treatment is delayed for at least about 2-42 daysafter discontinuation of the posaconazole regimen, or reduced for thetime period of about 2-42 days after discontinuation of the posaconazoleregimen.

In other embodiments in which the CYP3A4 substrate drug is tadalafil,the 72 hr dose of tadalafil is no more than about 10 mg, e.g., about 9.5mg, about 9.0 mg, about 8.5 mg, about 8.0 mg, about 7.5 mg, about 7.0mg, about 6.5 mg, about 6.0 mg, about 5.5 mg, about 5.0 mg, about 4.5mg, about 4.0 mg, about 3.5 mg, about 3.0 mg, about 2.5 mg, about 2.0mg, about 1.5 mg, about 1.0 mg, or about 0.5 mg, inclusive of all valuesand ranges therebetween, and treatment is delayed for at least about2-42 days after discontinuation of the posaconazole regimen, or reducedfor the time period of about 2-42 days after discontinuation of theposaconazole regimen.

In some embodiments, the CYP3A4 substrate drug is elotinib. In someembodiments, the reference dose for treating non-small cell lung cancer(NSCLC) is 150 mg per day. In some embodiments, the reference dose fortreating pancreatic cancer is 100 mg per day. In embodiments in whichthe CYP3A4 substrate drug is erlotinib, the daily dose of erlotinib isno more than about 150 mg, e.g., about 140 mg, about 130 mg, about 120mg, about 110 mg, about 100 mg, about 90 mg, about 80 mg, about 70 mg,about 60 mg, about 50 mg, about 40 mg, about 30 mg, about 20 mg, orabout 10 mg, inclusive of all values and ranges therebetween, andtreatment is delayed for at least about 2-42 days after discontinuationof the posaconazole regimen, or reduced for the time period of about2-42 days after discontinuation of the posaconazole regimen.

In embodiments in which the CYP3A4 substrate drug is solifenacinsuccinate, the daily dose of solifenacin succinate is no more than about10 mg, e.g., about 9 mg, about 8 mg, about 7 mg, about 6 mg, about 5 mg,about 4 mg, about 3 mg, about 2 mg, about 1 mg, or about 0.5 mg,inclusive of all values and ranges therebetween, and treatment isdelayed for at least about 2-42 days after discontinuation of theposaconazole regimen, or reduced for the time period of about 2-42 daysafter discontinuation of the posaconazole regimen.

In embodiments in which the CYP3A4 substrate drug is everolimus, thedaily dose of everolimus is no more than about 10 mg, e.g., about 9 mg,about 8 mg, about 7 mg, about 6 mg, about 5 mg, about 4 mg, about 3 mg,about 2 mg, about 1.75 mg, about 1.5 mg, about 1.25 mg, about 1.0 mg,about 0.75 mg, or about 0.5 mg, inclusive of all values and rangestherebetween, and treatment is delayed for at least about 2-42 daysafter discontinuation of the posaconazole regimen, or reduced for thetime period of about 2-42 days after discontinuation of the posaconazoleregimen.

In embodiments in which the CYP3A4 substrate drug is abemaciclib, thedaily dose of abemaciclib is no more than about 400 mg, e.g., about 350mg, about 300 mg, about 250 mg, about 225 mg, about 200 mg, about 175mg, about 150 mg, about 125 mg, about 100 mg, about 75 mg, about 50 mg,about 25 mg, about 10 mg, about 5 mg, about 1.0 mg, or about 0.5 mg,inclusive of all values and ranges therebetween, and treatment isdelayed for at least about 2-42 days after discontinuation of theposaconazole regimen, or reduced for the time period of about 2-42 daysafter discontinuation of the posaconazole regimen.

In embodiments in which the CYP3A4 substrate drug is ivacaftor, thedaily dose of ivacaftor is no more than about 300 mg, e.g., about 250mg, about 225 mg, about 200 mg, about 175 mg, about 150 mg, about 125mg, about 100 mg, about 75 mg, about 50 mg, about 25 mg, about 10 mg,about 5 mg, about 1.0 mg, or about 0.5 mg, inclusive of all values andranges therebetween, and treatment is delayed for at least about 2-42days after discontinuation of the posaconazole regimen, or reduced forthe time period of about 2-42 days after discontinuation of theposaconazole regimen.

In embodiments in which the CYP3A4 substrate drug is ruxolitinib, or apharmaceutically acceptable salt thereof (e.g., ruxolitinib phosphate),the daily dose of ruxolitinib phosphate is no more than about 50 mg,e.g., about 48 mg, about 45 mg, about 40 mg, about 35 mg, about 30 mg,about 25 mg, about 20 mg, about 15 mg, about 10 mg, about 5 mg, aboutabout 1.0 mg, about 0.75 mg, or about 0.5 mg, inclusive of all valuesand ranges therebetween, and treatment is delayed for at least about2-42 days after discontinuation of the posaconazole regimen, or reducedfor the time period of about 2-42 days after discontinuation of theposaconazole regimen.

In embodiments in which the CYP3A4 substrate drug is brexpiprazole, thedaily dose of brexpiprazole is no more than about 4 mg, e.g., about 3mg, about 2 mg, about 1.75 mg, about 1.5 mg, about 1.25 mg, about 1.0mg, about 0.75 mg, or about 0.5 mg, inclusive of all values and rangestherebetween, and treatment is delayed for at least about 2-42 daysafter discontinuation of the posaconazole regimen, or reduced for thetime period of about 2-42 days after discontinuation of the posaconazoleregimen.

In embodiments in which the CYP3A4 substrate drug isivacaftor/tezacaftor, the daily dose of tezactaftor is no more thanabout 100 mg, e.g., about 90 mg, about 80 mg, about 70 mg, about 60 mg,about 50 mg, about 40 mg, about 30 mg, about 20 mg, about 17.5 mg, about15 mg, about 12.5 mg, about 10 mg, about 7.5 mg, or about 5 mg,inclusive of all values and ranges therebetween, and the daily dose ofivacaftor is no more than about 300 mg, e.g., about 290 mg, about 280mg, about 270 mg, about 260 mg, about 250 mg, about 240 mg, about 230mg, about 220 mg, about 175 mg, about 150 mg, about 125 mg, about 100mg, about 75 mg, or about 50 mg, inclusive of all values and rangestherebetween, and treatment is delayed for at least about 2-42 daysafter discontinuation of the posaconazole regimen, or reduced for thetime period of about 2-42 days after discontinuation of the posaconazoleregimen.

In embodiments in which the CYP3A4 substrate drug is regorafenib, thedaily dose of regorafenib is no more than about 160 mg, e.g., about 150mg, about 140 mg, about 130 mg, about 120 mg, about 110 mg, about 100mg, about 90 mg, about 80 mg, about 70 mg, about 60 mg, about 50 mg,about 25 mg, about 10 mg, or about 5 mg, inclusive of all values andranges therebetween, and treatment is delayed for at least about 2-42days after discontinuation of the posaconazole regimen, or reduced forthe time period of about 2-42 days after discontinuation of theposaconazole regimen.

In embodiments in which the CYP3A4 substrate drug is daclatasvir, thedaily dose of daclatasvir is no more than about 90 mg, e.g., about 80mg, about 70 mg, about 60 mg, about 50 mg, about 40 mg, about 30 mg,about 20 mg, about 17.5 mg, about 15 mg, about 12.5 mg, about 10 mg,about 7.5 mg, or about 5 mg, inclusive of all values and rangestherebetween, and treatment is delayed for at least about 2-42 daysafter discontinuation of the posaconazole regimen, or reduced for thetime period of about 2-42 days after discontinuation of the posaconazoleregimen.

In embodiments in which the CYP3A4 substrate drug is crizotinib, thedaily dose of crizotinib is no more than about 500 mg, e.g., about 450mg, about 400 mg, about 350 mg, about 300 mg, about 250 mg, about 225mg, about 200 mg, about 175 mg, about 150 mg, about 125 mg, about 100mg, about 75 mg, about 50 mg, about 25 mg, about 10 mg, about 5 mg,about 1.0 mg, or about 0.5 mg, inclusive of all values and rangestherebetween, and treatment is delayed for at least about 2-42 daysafter discontinuation of the posaconazole regimen, or reduced for thetime period of about 2-42 days after discontinuation of the posaconazoleregimen.

In embodiments in which the CYP3A4 substrate drug is naloxegol or apharmaceutically acceptable salt thereof (e.g., naloxegol oxalate), thedaily dose of naloxegol oxalate is no more than about 25 mg, e.g., about22 mg, about 20 mg, about 18 mg, about 16 mg, about 15 mg, about 14 mg,about 13 mg, about 12 mg, about 10 mg, about 8 mg, about 5 mg, about 1mg, about 0.75 mg, or about 0.5 mg, inclusive of all values and rangestherebetween, and treatment is delayed for at least about 2-42 daysafter discontinuation of the posaconazole regimen, or reduced for thetime period of about 2-42 days after discontinuation of the posaconazoleregimen.

In embodiments in which the CYP3A4 substrate drug is dabrafenib, thedaily dose of dabrafenib is no more than about 300 mg, e.g., about 250mg, about 225 mg, about 200 mg, about 175 mg, about 150 mg, about 125mg, about 100 mg, about 75 mg, about 50 mg, about 25 mg, about 10 mg,about 5 mg, about 1.0 mg, or about 0.5 mg, inclusive of all values andranges therebetween, and treatment is delayed for at least about 2-42days after discontinuation of the posaconazole regimen, or reduced forthe time period of about 2-42 days after discontinuation of theposaconazole regimen.

In embodiments in which the CYP3A4 substrate drug is elbasvir andgrazoprevir, the daily dose of elbasvir is no more than about 1000 mg,e.g., about 900 mg, about 800 mg, about 700 mg, about 600 mg, about 500mg, about 400 mg, about 300 mg, about 200 mg, about 175 mg, about 150mg, about 125 mg, about 100 mg, about 75 mg, about 50 mg, or about 25mg, inclusive of all values and ranges therebetween, and the daily doseof grazoprevir is no more than about 2000 mg, e.g., about 1500 mg, about1250 mg, about 1000 mg, about 900 mg, about 800 mg, about 700 mg, about600 mg, about 500 mg, about 400 mg, about 300 mg, about 200 mg, about150 mg, about 100 mg, about 75 mg, or about 50 mg, inclusive of allvalues and ranges therebetween, and treatment is delayed for at leastabout 2-42 days after discontinuation of the posaconazole regimen, orreduced for the time period of about 2-42 days after discontinuation ofthe posaconazole regimen.

In addition to the preceding embodiments, the following embodimentsfurther illustrate methods of admisntering certain CYP3A4 substratedrugs of the present disclosure.

In some embodiments, the CYP3A4 substrate drug is abemaciclib. Thedisease or condition treated with abemaciclib can include any disease orcondition described herein or for which abemaciclib is indicated. Forexample, in some embodiments, abemaciclib is indicated in combinationwith an aromatase inhibitor as initial endocrine-based therapy for thetreatment of postmenopausal women with hormone receptor (HR)-positive,human epidermal growth factor receptor 2 (HER2)-negative advanced ormetastatic breast cancer. In some embodiments, abemaciclib is indicatedin combination with fulvestrant for the treatment of women with hormonereceptor (HR)-positive, human epidermal growth factor receptor 2(HER2)-negative advanced or metastatic breast cancer with diseaseprogression following endocrine therapy. In some embodiments,abemaciclib is indicated as monotherapy for the treatment of adultpatients with HR-positive, HER2-negative advanced or metastatic breastcancer with disease progression following endocrine therapy and priorchemotherapy in the metastatic setting. Abemaciclib may be administeredin a 50 mg, 100 mg, 150 mg, or 200 mg dosage form. In some embodiments,abemaciclib is administered twice daily up to a total daily dose of 400mg. For example, when abemaciclib is indicated in combination with anaromatase inhibitor as initial endocrine-based therapy for the treatmentof postmenopausal women with hormone receptor (HR)-positive, humanepidermal growth factor receptor 2 (HER2)-negative advanced ormetastatic breast cancer, the reference dose is 150 mg, administeredtwice daily (total daily reference dose is 300 mg). When abemaciclib isindicated in combination with fulvestrant for the treatment of womenwith hormone receptor (HR)-positive, human epidermal growth factorreceptor 2 (HER2)-negative advanced or metastatic breast cancer withdisease progression following endocrine therapy, the reference dose is150 mg, administered twice daily (total daily reference dose is 300 mg).When abemaciclib is indicated as monotherapy for the treatment of adultpatients with HR-positive, HER2-negative advanced or metastatic breastcancer with disease progression following endocrine therapy and priorchemotherapy in the metastatic setting, the reference dose is 200 mg,administered twice daily (total daily reference dose is 400 mg). Thus,in various embodiments, the total daily reference dose of abemaciclibmay be, for example, 25 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300mg, 350 mg, or 400 mg. In accordance with certain embodiments of thepresent disclosure, when the total daily reference dose of abemaciclibis, for example, 400 mg, the patient will take a reduced total dailydose of abemaciclib (either concomitantly with posaconazole or after adelay period after stopping posaconazole). In some embodiments, thereduced total daily dose of abemaciclib is, for example, 25 mg, 50 mg,75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg,300 mg, 325 mg, or 350 mg, including all integers and rangestherebetween. When the total daily reference dose of abemaciclib is 400mg, the reduced total daily dose of abemaciclib is, for example, 25 mg,50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg,275 mg, 300 mg, 325 mg, 350 mg, or 375 mg including all integers andranges therebetween. When the total daily reference dose of abemaciclibis 350 mg, the reduced total daily dose of abemaciclib is, for example,25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250mg, 275 mg, 300 mg, or 325 mg including all integers and rangestherebetween. When the total daily reference dose of abemaciclib is 300mg, the reduced total daily dose of abemaciclib is, for example, 25 mg,50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, or275 mg, including all integers and ranges therebetween. When the totaldaily reference dose of abemaciclib is 250 mg, the reduced total dailydose of abemaciclib is, for example, 25 mg, 50 mg, 75 mg, 100 mg, 125mg, 150 mg, 175 mg, 200 mg, or 225 mg, including all integers and rangestherebetween. When the total daily reference dose of abemaciclib is 200mg, the reduced total daily dose of abemaciclib is, for example, 25 mg,50 mg, 75 mg, 100 mg, 125 mg, 150 mg, or 175 mg, including all integersand ranges therebetween. When the total daily reference dose ofabemaciclib is 150 mg, the reduced total daily dose of abemaciclib is,for example, 25 mg, 50 mg, 75 mg, 100 mg, or 125 mg, including allintegers and ranges therebetween. When the total daily reference dose ofabemaciclib is 100 mg, the reduced total daily dose of abemaciclib is,for example, 25 mg, 50 mg or 75 mg, including all integers and rangestherebetween. Correspondingly, when the individual reference dose ofabemaciclib is 200 mg, the reduced individual reference dose ofabemaciclib is, for example, 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150mg, or 175 mg, including all integers and ranges therebetween. When theindividual reference dose of abemaciclib is 150 mg, the reducedindividual reference dose of abemaciclib is, for example, 25 mg, 50 mg,75 mg, 100 mg, or 125 mg, including all integers and rangestherebetween.

In some embodiments, the CYP3A4 substrate drug is ado-trastuzumabemtansine. The disease or condition treated with ado-trastuzumabemtansine can include any disease or condition described herein or forwhich ado-trastuzumab emtansine is indicated. For example, in someembodiments, ado-trastuzumab emtansine is indicated as a single agent,for the treatment of patients with HER2-positive, metastatic breastcancer who previously received trastuzumab and a taxane, separately orin combination and the patients should have either received priortherapy for metastatic disease or developed disease recurrence during orwithin six months of completing adjuvant therapy. Ado-trastuzumabemtansine may be administered in via intravenous infusion in a 2.4mg/kg, 3 mg/kg, or 3.6 mg/kg dosage form. In some embodiments,ado-trastuzumab emtansine is administered once every three weeks up to atotal dose of 3.6 mg/kg every three weeks. For example, whenado-trastuzumab emtansine is indicated as a single agent, for thetreatment of patients with HER2-positive, metastatic breast cancer whopreviously received trastuzumab and a taxane, separately or incombination and the patients should have either received prior therapyfor metastatic disease or developed disease recurrence during or withinsix months of completing adjuvant therapy, the reference dose is 3.6mg/kg every three weeks (total reference dose is 3.6 mg/kg every threeweeks). Thus, in various embodiments, the total daily reference dose ofado-trastuzumab emtansine may be, for example, 0.3 mg/kg every threeweeks, 0.6 mg/kg every three weeks, 0.9 mg/kg every three weeks, 1.2mg/kg every three weeks, 1.5 mg/kg every three weeks, 1.8 mg/kg everythree weeks, 2.1 mg/kg every three weeks, 2.4 mg/kg every three weeks,2.7 mg/kg every three weeks, 3.0 mg/kg every three weeks, 3.3 mg/kgevery three weeks, or 3.6 mg/kg every three weeks. In accordance withcertain embodiments of the present disclosure, when the total dailyreference dose of ado-trastuzumab emtansine is, for example, 3.6 mg/kgevery three weeks, the patient will take a reduced total daily dose ofado-trastuzumab emtansine (either concomitantly with posaconazole orafter a delay period after stopping posaconazole). In some embodiments,the reduced total daily dose of ado-trastuzumab emtansine is, forexample, 0.3 mg/kg every three weeks, 0.6 mg/kg every three weeks, 0.9mg/kg every three weeks, 1.2 mg/kg every three weeks, 1.5 mg/kg everythree weeks, 1.8 mg/kg every three weeks, 2.1 mg/kg every three weeks,2.4 mg/kg every three weeks, 2.7 mg/kg every three weeks, 3.0 mg/kgevery three weeks, 3.3 mg/kg every three weeks, including all integersand ranges therebetween. When the total daily reference dose ofado-trastuzumab emtansine is 3.6 mg/kg every three weeks, the reducedtotal daily dose of ado-trastuzumab emtansine is, for example, 0.3 mg/kgevery three weeks, 0.6 mg/kg every three weeks, 0.9 mg/kg every threeweeks, 1.2 mg/kg every three weeks, 1.5 mg/kg every three weeks, 1.8mg/kg every three weeks, 2.1 mg/kg every three weeks, 2.4 mg/kg everythree weeks, 2.7 mg/kg every three weeks, 3.0 mg/kg every three weeks,3.3 mg/kg every three weeks, including all integers and rangestherebetween. When the total daily reference dose of ado-trastuzumabemtansine is 3.0 mg/kg every three weeks, the reduced total daily doseof ado-trastuzumab emtansine is, for example, 0.3 mg/kg every threeweeks, 0.6 mg/kg every three weeks, 0.9 mg/kg every three weeks, 1.2mg/kg every three weeks, 1.5 mg/kg every three weeks, 1.8 mg/kg everythree weeks, 2.1 mg/kg every three weeks, 2.4 mg/kg every three weeks,or 2.7 mg/kg every three weeks, including all integers and rangestherebetween. When the total daily reference dose of ado-trastuzumabemtansine is 2.4 mg/kg every three weeks, the reduced total daily doseof ado-trastuzumab emtansine is, for example, 0.3 mg/kg every threeweeks, 0.6 mg/kg every three weeks, 0.9 mg/kg every three weeks, 1.2mg/kg every three weeks, 1.5 mg/kg every three weeks, 1.8 mg/kg everythree weeks, or 2.1 mg/kg every three weeks, including all integers andranges therebetween.

In some embodiments, the CYP3A4 substrate drug is apalutamide. Thedisease or condition treated with apalutamide can include any disease orcondition described herein or for which apalutamide is indicated. Forexample, in some embodiments, apalutamide is indicated for the treatmentof patients with non-metastatic castration-resistant prostate cancer.Apalutamide may be administered in a 60 mg dosage form. In someembodiments, apalutamide is administered once daily up to a total dailydose of 240 mg. For example, when apalutamide is indicated for thetreatment of patients with non-metastatic castration-resistant prostatecancer, the reference dose is 240 mg, administered once daily (totaldaily reference dose is 240 mg. Thus, in various embodiments, the totaldaily reference dose of apalutamide may be, for example, 30 mg, 60 mg,90 mg, 120 mg, 150 mg, 180 mg, 210 mg, or 240 mg. In accordance withcertain embodiments of the present disclosure, when the total dailyreference dose of apalutamide is, for example, 240 mg, the patient willtake a reduced total daily dose of apalutamide (either concomitantlywith posaconazole or after a delay period after stopping posaconazole).In some embodiments, the reduced total daily dose of apalutamide is, forexample, 30 mg, 60 mg, 90 mg, 120 mg, 150 mg, 180 mg, or 210 mg,including all integers and ranges therebetween. When the total dailyreference dose of apalutamide is 240 mg, the reduced total daily dose ofapalutamide is, for example, 30 mg, 60 mg, 90 mg, 120 mg, 150 mg, 180mg, or 210 mg, including all integers and ranges therebetween. When thetotal daily reference dose of apalutamide is 180 mg, the reduced totaldaily dose of apalutamide is, for example, 30 mg, 60 mg, 90 mg, 120 mg,or 150 mg, including all integers and ranges therebetween. When thetotal daily reference dose of apalutamide is 120 mg, the reduced totaldaily dose of apalutamide is, for example, 30 mg, 60 mg, or 90 mg,including all integers and ranges therebetween. Correspondingly, whenthe individual reference dose of apalutamide is 60 mg, the reducedindividual reference dose of apalutamide is, for example, 30 mg.

In some embodiments, the CYP3A4 substrate drug is aripiprazole(ABILIFY®). The disease or condition treated with aripiprazole caninclude any disease or condition described herein or for whicharipiprazole is indicated. For example, in some embodiments,aripiprazole is indicated orally for schizophrenia. In some embodiments,aripiprazole is indicated orally for Acute Treatment of Manic and MixedEpisodes associated with Bipolar I. In some embodiments, aripiprazole isindicated orally for Adjunctive Treatment of Major Depressive Disorder.In some embodiments, aripiprazole is indicated orally for IrritabilityAssociated with Autistic Disorder. In some embodiments, aripiprazole isindicated orally for the Treatment of Tourette's Disorder. In someembodiments, aripiprazole is indicated for intramuscular injection forAgitation associated with schizophrenia or bipolar mania. Aripiprazolemay be administered in a 2 mg, 5 mg, 10 mg, 15 mg, 20 mg, and 30 mgtablet dosage form or a 10 mg or 15 mg orally disintegrating tablet or a1 mg/mL oral solution or a 9.75 mg/1.3 mL single-dose vial. In someembodiments, aripiprazole is administered once daily up to a total dailydose of 30 mg (orally or via injection). For example, when aripiprazoleis indicated for schizophrenia in adults, the initial reference dose is10-15 mg administered once daily (total daily reference dose is 10-15mg). When aripiprazole is indicated for schizophrenia in adults, therecommended reference dose is 10-15 mg administered once daily (totaldaily reference dose is 10-15 mg). When aripiprazole is indicated forschizophrenia in adults, the maximum reference dose is 30 mgadministered once daily (total daily reference dose is 30 mg). Forexample, when aripiprazole is indicated for schizophrenia inadolescents, the initial reference dose is 2 mg administered once daily(total daily reference dose is 2 mg). When aripiprazole is indicated forschizophrenia in adolescents, the recommended reference dose is 10 mgadministered once daily (total daily reference dose is 10 mg). Whenaripiprazole is indicated for schizophrenia in adolescents, the maximumreference dose is 30 mg administered once daily (total daily referencedose is 30 mg). For example, when aripiprazole is indicated for bipolarmania in adults (monotherapy), the initial reference dose is 15 mgadministered once daily (total daily reference dose is 15 mg). Whenaripiprazole is indicated for bipolar mania in adults (monotherapy), therecommended reference dose is 15 mg administered once daily (total dailyreference dose is 15 mg). When aripiprazole is indicated for bipolarmania in adults (monotherapy), the maximum reference dose is 30 mgadministered once daily (total daily reference dose is 30 mg). Forexample, when aripiprazole is indicated for bipolar mania in adults(adjunct to lithium or valproate), the initial reference dose is 10-15mg administered once daily (total daily reference dose is 10-15 mg).When aripiprazole is indicated for bipolar mania in adults (adjunct tolithium or valproate), the recommended reference dose is 15 mgadministered once daily (total daily reference dose is 15 mg). Whenaripiprazole is indicated for bipolar mania in adults (adjunct tolithium or valproate), the maximum reference dose is 30 mg administeredonce daily (total daily reference dose is 30 mg). For example, whenaripiprazole is indicated for bipolar mania in pediatrics (monotherapyor adjunct to lithium or valproate), the initial reference dose is 2 mgadministered once daily (total daily reference dose is 2 mg). Whenaripiprazole is indicated for bipolar mania in pediatrics (monotherapyor adjunct to lithium or valproate), the recommended reference dose is10 mg administered once daily (total daily reference dose is 10 mg).When aripiprazole is indicated for bipolar mania in pediatrics(monotherapy or adjunct to lithium or valproate), the maximum referencedose is 30 mg administered once daily (total daily reference dose is 30mg). For example, when aripiprazole is indicated for major depressivedisorder in adults (adjunct to antidepressants), the initial referencedose is 2-5 mg administered once daily (total daily reference dose is2-5 mg). When aripiprazole is indicated for major depressive disorder inadults (adjunct to antidepressants), the recommended reference dose is5-10 mg administered once daily (total daily reference dose is 5-10 mg).When aripiprazole is indicated for major depressive disorder in adults(adjunct to antidepressants), the maximum reference dose is 15 mgadministered once daily (total daily reference dose is 15 mg). Forexample, when aripiprazole is indicated for irritability associated withautistic disorder in pediatric patients, the initial reference dose is 2mg administered once daily (total daily reference dose is 2 mg). Whenaripiprazole is indicated for irritability associated with autisticdisorder in pediatric patients, the recommended reference dose is 5-10mg administered once daily (total daily reference dose is 5-10 mg). Whenaripiprazole is indicated for irritability associated with autisticdisorder in pediatric patients, the maximum reference dose is 15 mgadministered once daily (total daily reference dose is 15 mg). Forexample, when aripiprazole is indicated for Tourette's disorder inpatients <50 kg, the initial reference dose is 2 mg administered oncedaily (total daily reference dose is 2 mg). When aripiprazole isindicated for Tourette's disorder in patients <50 kg, the recommendedreference dose is 5 mg administered once daily (total daily referencedose is 5 mg). When aripiprazole is indicated for Tourette's disorder inpatients <50 kg, the maximum reference dose is 10 mg administered oncedaily (total daily reference dose is 10 mg). For example, whenaripiprazole is indicated for Tourette's disorder in patients ≥50 kg,the initial reference dose is 2 mg administered once daily (total dailyreference dose is 2 mg). When aripiprazole is indicated for Tourette'sdisorder in patients ≥50 kg, the recommended reference dose is 10 mgadministered once daily (total daily reference dose is 10 mg). Whenaripiprazole is indicated for Tourette's disorder in patients ≥50 kg,the maximum reference dose is 20 mg administered once daily (total dailyreference dose is 20 mg). For example, when aripiprazole is indicatedfor agitation associated with schizophrenia or bipolar mania in adults,the initial reference dose is 9.75 mg/1.3 mL administeredintramuscularly once daily (total daily reference dose is 9.75 mg/1.3mL). When aripiprazole is indicated for agitation associated withschizophrenia or bipolar mania in adults, the maximum reference dose is30 mg administered intramuscularly once daily (total daily referencedose is 30 mg) Thus, in various embodiments, the total daily referencedose of aripiprazole may be, for example, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg,6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg,17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27mg, 28 mg, 29 mg, or 30 mg. In accordance with certain embodiments ofthe present disclosure, when the total daily reference dose ofaripiprazole is, for example, 30 mg, the patient will take a reducedtotal daily dose of aripiprazole (either concomitantly with posaconazoleor after a delay period after stopping posaconazole). In someembodiments, the reduced total daily dose of aripiprazole is, forexample, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, or 29 mg, includingall integers and ranges therebetween. When the total daily referencedose of aripiprazole is 30 mg, the reduced total daily dose ofaripiprazole is, for example, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg,8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28mg, or 29 mg, including all integers and ranges therebetween. When thetotal daily reference dose of aripiprazole is 20 mg, the reduced totaldaily dose of aripiprazole is, for example, 1 mg, 2 mg, 3 mg, 4 mg, 5mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16mg, 17 mg, 18 mg, or 19 mg, including all integers and rangestherebetween. When the total daily reference dose of aripiprazole is 15mg, the reduced total daily dose of aripiprazole is, for example, 1 mg,2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13mg, or 14 mg, including all integers and ranges therebetween. When thetotal daily reference dose of aripiprazole is 10 mg, the reduced totaldaily dose of aripiprazole is, for example, 1 mg, 2 mg, 3 mg, 4 mg, 5mg, 6 mg, 7 mg, 8 mg, or 9 mg, including all integers and rangestherebetween. When the total daily reference dose of aripiprazole is 5mg, the reduced total daily dose of aripiprazole is, for example, 1 mg,2 mg, 3 mg, or 4 mg, including all integers and ranges therebetween.When the total daily reference dose of aripiprazole is 2 mg, the reducedtotal daily dose of aripiprazole is, for example, 1 mg. Correspondingly,when the individual reference dose of aripiprazole is 30 mg, the reducedindividual reference dose of aripiprazole is, for example, 1 mg, 2 mg, 3mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24mg, 25 mg, 26 mg, 27 mg, 28 mg, or 29 mg, including all integers andranges therebetween. When the individual reference dose of aripiprazoleis 20 mg, the reduced individual reference dose of aripiprazole is, forexample, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, or 19 mg, includingall integers and ranges therebetween. When the individual reference doseof aripiprazole is 10 mg, the reduced individual reference dose ofaripiprazole is, for example, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg,8 mg, or 9 mg, including all integers and ranges therebetween. When theindividual reference dose of aripiprazole is 5 mg, the reducedindividual reference dose of aripiprazole is, for example, 1 mg, 2 mg, 3mg, or 4 mg, including all integers and ranges therebetween. When theindividual reference dose of aripiprazole is 2 mg, the reducedindividual reference dose of aripiprazole is, for example, 1 mg.

In some embodiments, the CYP3A4 substrate drug is aripiprazole(ARISTADA®). The disease or condition treated with aripiprazole caninclude any disease or condition described herein or for whicharipiprazole is indicated. For example, in some embodiments,aripiprazole is indicated for the treatment of schizophrenia.Aripiprazole may be administered in a 441 mg, 662 mg, 882 mg, or 1064single-use pre-filled syringe. In some embodiments, aripiprazole isadministered once per month up to a total dose of 882 mg. In someembodiments, aripiprazole is administered once every 6 weeks up to atotal dose of 882 mg. In some embodiments, aripiprazole is administeredonce every 2 months up to a total dose of 1064 mg. For example, whenaripiprazole is indicated for the treatment of schizophrenia, thereference dose is 441 mg, 662 mg or 882 mg administered monthly, 882 mgdose every 6 weeks, or 1064 mg dose every 2 months, (total referencedose is 441 mg monthly, 662 mg monthly, 882 mg, monthly, 882 mg every 6weeks, or 1064 mg every 2 months). Thus, in various embodiments, thetotal reference dose of aripiprazole may be, for example, 441 mgmonthly, 662 mg monthly, 882 mg, monthly, 882 mg every 6 weeks, or 1064mg every 2 months. In accordance with certain embodiments of the presentdisclosure, when the total daily reference dose of aripiprazole is, forexample, 1064 mg every 2 months, the patient will take a reduced totaldaily dose of aripiprazole (either concomitantly with posaconazole orafter a delay period after stopping posaconazole). In some embodiments,the reduced total daily dose of aripiprazole is, for example, 10 mgmonthly, 20 mg monthly, 30 mg monthly, 40 mg monthly, 50 mg monthly, 60mg monthly, 70 mg monthly, 80 mg monthly, 90 mg monthly, 100 mg monthly,120 mg monthly, 140 mg monthly, 160 mg monthly, 180 mg monthly, 200 mgmonthly, 220 mg monthly, 240 mg monthly, 260 mg monthly, 280 mg monthly,300 mg monthly, 320 mg monthly, 340 mg monthly, 360 mg monthly, 380 mgmonthly, 400 mg monthly, 420 mg monthly, 440 mg monthly, 460 mg monthly,480 mg monthly, 500 mg monthly, 520 mg monthly, 540 mg monthly, 560 mgmonthly, 580 mg monthly, 600 mg monthly, 620 mg monthly, 640 mg monthly,660 mg monthly, 680 mg monthly, 700 mg monthly, 720 mg monthly, 740 mgmonthly, 760 mg monthly, 780 mg monthly, 800 mg monthly, 820 mg monthly,840 mg monthly, 860 mg monthly, or 880 mg monthly, including allintegers and ranges therebetween; or 10 mg every 6 weeks, 20 mg every 6weeks, 30 mg every 6 weeks, 40 mg every 6 weeks, 50 mg every 6 weeks, 60mg every 6 weeks, 70 mg every 6 weeks, 80 mg every 6 weeks, 90 mg every6 weeks, 100 mg every 6 weeks, 120 mg every 6 weeks, 140 mg every 6weeks, 160 mg every 6 weeks, 180 mg every 6 weeks, 200 mg every 6 weeks,220 mg every 6 weeks, 240 mg every 6 weeks, 260 mg every 6 weeks, 280 mgevery 6 weeks, 300 mg every 6 weeks, 320 mg every 6 weeks, 340 mg every6 weeks, 360 mg every 6 weeks, 380 mg every 6 weeks, 400 mg every 6weeks, 420 mg every 6 weeks, 440 mg every 6 weeks, 460 mg every 6 weeks,480 mg every 6 weeks, 500 mg every 6 weeks, 520 mg every 6 weeks, 540 mgevery 6 weeks, 560 mg every 6 weeks, 580 mg every 6 weeks, 600 mg every6 weeks, 620 mg every 6 weeks, 640 mg every 6 weeks, 660 mg every 6weeks, 680 mg every 6 weeks, 700 mg every 6 weeks, 720 mg every 6 weeks,740 mg every 6 weeks, 760 mg every 6 weeks, 780 mg every 6 weeks, 800 mgevery 6 weeks, 820 mg every 6 weeks, 840 mg every 6 weeks, 860 mg every6 weeks, or 880 mg every 6 weeks, including all integers and rangestherebetween; or 10 mg every 2 months, 20 mg every 2 months, 30 mg every2 months, 40 mg every 2 months, 50 mg every 2 months, 60 mg every 2months, 70 mg every 2 months, 80 mg every 2 months, 90 mg every 2months, 100 mg every 2 months, 120 mg every 2 months, 140 mg every 2months, 160 mg every 2 months, 180 mg every 2 months, 200 mg every 2months, 220 mg every 2 months, 240 mg every 2 months, 260 mg every 2months, 280 mg every 2 months, 300 mg every 2 months, 320 mg every 2months, 340 mg every 2 months, 360 mg every 2 months, 380 mg every 2months, 400 mg every 2 months, 420 mg every 2 months, 440 mg every 2months, 460 mg every 2 months, 480 mg every 2 months, 500 mg every 2months, 520 mg every 2 months, 540 mg every 2 months, 560 mg every 2months, 580 mg every 2 months, 600 mg every 2 months, 620 mg every 2months, 640 mg every 2 months, 660 mg every 2 months, 680 mg every 2months, 700 mg every 2 months, 720 mg every 2 months, 740 mg every 2months, 760 mg every 2 months, 780 mg every 2 months, 800 mg every 2months, 820 mg every 2 months, 840 mg every 2 months, 860 mg every 2months, or 880 mg every 2 months, 900 mg every 2 months, 920 mg every 2months, 940 mg every 2 months, 960 mg every 2 months, 980 mg every 2months, 1000 mg every 2 months, 1020 mg every 2 months, 1040 mg every 2months or 1060 mg every 2 months, including all integers and rangestherebetween. When the total reference dose of aripiprazole is 1064 mgevery 2 months, the reduced total daily dose of aripiprazole is, forexample, 10 mg every 2 months, 20 mg every 2 months, 30 mg every 2months, 40 mg every 2 months, 50 mg every 2 months, 60 mg every 2months, 70 mg every 2 months, 80 mg every 2 months, 90 mg every 2months, 100 mg every 2 months, 120 mg every 2 months, 140 mg every 2months, 160 mg every 2 months, 180 mg every 2 months, 200 mg every 2months, 220 mg every 2 months, 240 mg every 2 months, 260 mg every 2months, 280 mg every 2 months, 300 mg every 2 months, 320 mg every 2months, 340 mg every 2 months, 360 mg every 2 months, 380 mg every 2months, 400 mg every 2 months, 420 mg every 2 months, 440 mg every 2months, 460 mg every 2 months, 480 mg every 2 months, 500 mg every 2months, 520 mg every 2 months, 540 mg every 2 months, 560 mg every 2months, 580 mg every 2 months, 600 mg every 2 months, 620 mg every 2months, 640 mg every 2 months, 660 mg every 2 months, 680 mg every 2months, 700 mg every 2 months, 720 mg every 2 months, 740 mg every 2months, 760 mg every 2 months, 780 mg every 2 months, 800 mg every 2months, 820 mg every 2 months, 840 mg every 2 months, 860 mg every 2months, or 880 mg every 2 months, 900 mg every 2 months, 920 mg every 2months, 940 mg every 2 months, 960 mg every 2 months, 980 mg every 2months, 1000 mg every 2 months, 1020 mg every 2 months, 1040 mg every 2months or 1060 mg every 2 months, including all integers and rangestherebetween. When the total reference dose of aripiprazole is 882 mgevery 6 weeks, the reduced total dose of aripiprazole is, for example,10 mg every 6 weeks, 20 mg every 6 weeks, 30 mg every 6 weeks, 40 mgevery 6 weeks, 50 mg every 6 weeks, 60 mg every 6 weeks, 70 mg every 6weeks, 80 mg every 6 weeks, 90 mg every 6 weeks, 100 mg every 6 weeks,120 mg every 6 weeks, 140 mg every 6 weeks, 160 mg every 6 weeks, 180 mgevery 6 weeks, 200 mg every 6 weeks, 220 mg every 6 weeks, 240 mg every6 weeks, 260 mg every 6 weeks, 280 mg every 6 weeks, 300 mg every 6weeks, 320 mg every 6 weeks, 340 mg every 6 weeks, 360 mg every 6 weeks,380 mg every 6 weeks, 400 mg every 6 weeks, 420 mg every 6 weeks, 440 mgevery 6 weeks, 460 mg every 6 weeks, 480 mg every 6 weeks, 500 mg every6 weeks, 520 mg every 6 weeks, 540 mg every 6 weeks, 560 mg every 6weeks, 580 mg every 6 weeks, 600 mg every 6 weeks, 620 mg every 6 weeks,640 mg every 6 weeks, 660 mg every 6 weeks, 680 mg every 6 weeks, 700 mgevery 6 weeks, 720 mg every 6 weeks, 740 mg every 6 weeks, 760 mg every6 weeks, 780 mg every 6 weeks, 800 mg every 6 weeks, 820 mg every 6weeks, 840 mg every 6 weeks, 860 mg every 6 weeks, or 880 mg every 6weeks, including all integers and ranges therebetween. When the totalreference dose of aripiprazole is 882 mg monthly, the reduced total doseof aripiprazole is, for example, 10 mg monthly, 20 mg monthly, 30 mgmonthly, 40 mg monthly, 50 mg monthly, 60 mg monthly, 70 mg monthly, 80mg monthly, 90 mg monthly, 100 mg monthly, 120 mg monthly, 140 mgmonthly, 160 mg monthly, 180 mg monthly, 200 mg monthly, 220 mg monthly,240 mg monthly, 260 mg monthly, 280 mg monthly, 300 mg monthly, 320 mgmonthly, 340 mg monthly, 360 mg monthly, 380 mg monthly, 400 mg monthly,420 mg monthly, 440 mg monthly, 460 mg monthly, 480 mg monthly, 500 mgmonthly, 520 mg monthly, 540 mg monthly, 560 mg monthly, 580 mg monthly,600 mg monthly, 620 mg monthly, 640 mg monthly, 660 mg monthly, 680 mgmonthly, 700 mg monthly, 720 mg monthly, 740 mg monthly, 760 mg monthly,780 mg monthly, 800 mg monthly, 820 mg monthly, 840 mg monthly, 860 mgmonthly, or 880 mg monthly, including all integers and rangestherebetween. When the total reference dose of aripiprazole is 662 mgmonthly, the reduced total dose of aripiprazole is, for example, 10 mgmonthly, 20 mg monthly, 30 mg monthly, 40 mg monthly, 50 mg monthly, 60mg monthly, 70 mg monthly, 80 mg monthly, 90 mg monthly, 100 mg monthly,120 mg monthly, 140 mg monthly, 160 mg monthly, 180 mg monthly, 200 mgmonthly, 220 mg monthly, 240 mg monthly, 260 mg monthly, 280 mg monthly,300 mg monthly, 320 mg monthly, 340 mg monthly, 360 mg monthly, 380 mgmonthly, 400 mg monthly, 420 mg monthly, 440 mg monthly, 460 mg monthly,480 mg monthly, 500 mg monthly, 520 mg monthly, 540 mg monthly, 560 mgmonthly, 580 mg monthly, 600 mg monthly, 620 mg monthly, 640 mg monthly,or 660 mg monthly, including all integers and ranges therebetween. Whenthe total reference dose of aripiprazole is 441 mg monthly, the reducedtotal dose of aripiprazole is, for example, 10 mg monthly, 20 mgmonthly, 30 mg monthly, 40 mg monthly, 50 mg monthly, 60 mg monthly, 70mg monthly, 80 mg monthly, 90 mg monthly, 100 mg monthly, 120 mgmonthly, 140 mg monthly, 160 mg monthly, 180 mg monthly, 200 mg monthly,220 mg monthly, 240 mg monthly, 260 mg monthly, 280 mg monthly, 300 mgmonthly, 320 mg monthly, 340 mg monthly, 360 mg monthly, 380 mg monthly,400 mg monthly, 420 mg monthly, or 440 mg monthly, including allintegers and ranges therebetween.

In some embodiments, the CYP3A4 substrate drug is aripiprazole (ABILIFYMAINTENA®). The disease or condition treated with aripiprazole caninclude any disease or condition described herein or for whicharipiprazole is indicated. For example, in some embodiments,aripiprazole is indicated for the treatment of schizophrenia in adults.In some embodiments, aripiprazole is indicated as a maintenancemonotherapy treatment of bipolar I disorder in adults. Aripiprazole maybe administered in 160, 200 mg, 300 mg or 400 mg injection. In someembodiments, aripiprazole is administered once monthly up to a totaldaily dose of 400 mg. For example, when aripiprazole is indicated forschizophrenia in adults, the reference dose is 400 mg, administered oncemonthly (total daily reference dose is 400 mg monthly). For example,when aripiprazole is indicated as a maintenance monotherapy treatment ofbipolar I disorder in adults, the reference dose is 400 mg, administeredonce monthly (total daily reference dose is 400 mg monthly). Thus, invarious embodiments, the total reference dose of aripiprazole may be,for example, 160 mg monthly, 200 mg monthly, 300 mg monthly, or 400 mgmonthly. In accordance with certain embodiments of the presentdisclosure, when the total daily reference dose of aripiprazole is, forexample, 400 mg monthly, the patient will take a reduced total dailydose of aripiprazole (either concomitantly with posaconazole or after adelay period after stopping posaconazole). In some embodiments, thereduced total dose of aripiprazole is, for example, 10 mg monthly, 20 mgmonthly, 30 mg monthly, 40 mg monthly, 50 mg monthly, 60 mg monthly, 70mg monthly, 80 mg monthly, 90 mg monthly, 100 mg monthly, 110 mgmonthly, 120 mg monthly, 130 mg monthly, 140 mg monthly, 150 mg monthly,160 mg monthly, 170 mg monthly, 180 mg monthly, 190 mg monthly, 200 mgmonthly, 210 mg monthly, 220 mg monthly, 230 mg monthly, 240 mg monthly,250 mg monthly, 260 mg monthly, 270 mg monthly, 280 mg monthly, 290 mgmonthly, 300 mg monthly, 310 mg monthly, 320 mg monthly, 330 mg monthly,340 mg monthly, 350 mg monthly, 360 mg monthly, 370 mg monthly, 380 mgmonthly, or 390 mg monthly. When the total reference dose ofaripiprazole is 400 mg monthly, the reduced total dose of aripiprazoleis 10 mg monthly, 20 mg monthly, 30 mg monthly, 40 mg monthly, 50 mgmonthly, 60 mg monthly, 70 mg monthly, 80 mg monthly, 90 mg monthly, 100mg monthly, 110 mg monthly, 120 mg monthly, 130 mg monthly, 140 mgmonthly, 150 mg monthly, 160 mg monthly, 170 mg monthly, 180 mg monthly,190 mg monthly, 200 mg monthly, 210 mg monthly, 220 mg monthly, 230 mgmonthly, 240 mg monthly, 250 mg monthly, 260 mg monthly, 270 mg monthly,280 mg monthly, 290 mg monthly, 300 mg monthly, 310 mg monthly, 320 mgmonthly, 330 mg monthly, 340 mg monthly, 350 mg monthly, 360 mg monthly,370 mg monthly, 380 mg monthly, or 390 mg monthly, including allintegers and ranges therebetween. When the total reference dose ofaripiprazole is 300 mg monthly, the reduced total dose of aripiprazoleis, for example, 10 mg monthly, 20 mg monthly, 30 mg monthly, 40 mgmonthly, 50 mg monthly, 60 mg monthly, 70 mg monthly, 80 mg monthly, 90mg monthly, 100 mg monthly, 110 mg monthly, 120 mg monthly, 130 mgmonthly, 140 mg monthly, 150 mg monthly, 160 mg monthly, 170 mg monthly,180 mg monthly, 190 mg monthly, 200 mg monthly, 210 mg monthly, 220 mgmonthly, 230 mg monthly, 240 mg monthly, 250 mg monthly, 260 mg monthly,270 mg monthly, 280 mg monthly, or 290 mg monthly, including allintegers and ranges therebetween. When the total reference dose ofaripiprazole is 200 mg monthly, the reduced total dose of aripiprazoleis, for example, 10 mg monthly, 20 mg monthly, 30 mg monthly, 40 mgmonthly, 50 mg monthly, 60 mg monthly, 70 mg monthly, 80 mg monthly, 90mg monthly, 100 mg monthly, 110 mg monthly, 120 mg monthly, 130 mgmonthly, 140 mg monthly, 150 mg monthly, 160 mg monthly, 170 mg monthly,180 mg monthly, or 190 mg monthly, including all integers and rangestherebetween. When the total reference dose of aripiprazole is 160 mgmonthly, the reduced total dose of aripiprazole is, for example, 10 mgmonthly, 20 mg monthly, 30 mg monthly, 40 mg monthly, 50 mg monthly, 60mg monthly, 70 mg monthly, 80 mg monthly, 90 mg monthly, 100 mg monthly,110 mg monthly, 120 mg monthly, 130 mg monthly, 140 mg monthly, or 150mg monthly, 160 mg monthly, including all integers and rangestherebetween.

In some embodiments, the CYP3A4 substrate drug is bosutinib. The diseaseor condition treated with bosutinib can include any disease or conditiondescribed herein or for which bosutinib is indicated. For example, insome embodiments, bosutinib is indicated for Newly-diagnosed chronicphase Ph+ chronic myelogenous leukemia (CML). In some embodiments,bosutinib is indicated for Chronic, accelerated, or blast phase Ph+ CMLwith resistance or intolerance to prior therapy. Bosutinib may beadministered in a 100 mg, 400 mg, or 500 mg dosage form. In someembodiments, bosutinib is administered once daily up to a total dailydose of 600 mg. For example, when bosutinib is indicated forNewly-diagnosed chronic phase Ph+ chronic myelogenous leukemia (CML),the reference dose is 400 mg, administered once daily (total dailyreference dose is 400 mg). For example, when bosutinib is indicated forChronic, accelerated, or blast phase Ph+ CML with resistance orintolerance to prior therapy, the reference dose is 500 mg, administeredonce daily (total daily reference dose is 500 mg). In some embodiments,the dose is escalated by increments of 100 mg once daily to a maximum of600 mg daily in patients who do not reach complete hematologic,cytogenetic, or molecular response and do not have Grade 3 or greateradverse reactions. Thus, in various embodiments, the total dailyreference dose of bosutinib may be, for example, 50 mg, 100 mg, 150 mg,200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, or 600mg. In accordance with certain embodiments of the present disclosure,when the total daily reference dose of bosutinib is, for example, 600 mgthe patient will take a reduced total daily dose of bosutinib (eitherconcomitantly with posaconazole or after a delay period after stoppingposaconazole). In some embodiments, the reduced total daily dose ofbosutinib is, for example, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300mg, 350 mg, 400 mg, 450 mg, 500 mg, or 550 mg, including all integersand ranges therebetween. When the total daily reference dose ofbosutinib is 600 mg, the reduced total daily dose of bosutinib is, forexample, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg,450 mg, 500 mg, or 550 mg, including all integers and rangestherebetween. When the total daily reference dose of bosutinib is 500mg, the reduced total daily dose of bosutinib is, for example, 50 mg,100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, or 450 mg,including all integers and ranges therebetween. When the total dailyreference dose of bosutinib is 400 mg, the reduced total daily dose ofbosutinib is, for example, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300mg, or 350 mg, including all integers and ranges therebetween.Correspondingly, when the individual reference dose of bosutinib is 500mg, the reduced individual reference dose of bosutinib is, for example,50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, or 450mg, including all integers and ranges therebetween. When the individualreference dose of bosutinib is 400 mg, the reduced individual referencedose of bosutinib is, for example, 50 mg, 100 mg, 150 mg, 200 mg, 250mg, 300 mg, or 350 mg, including all integers and ranges therebetween.

In some embodiments, the CYP3A4 substrate drug is brexpiprazole. Thedisease or condition treated with brexpiprazole can include any diseaseor condition described herein or for which brexpiprazole is indicated.For example, in some embodiments, brexpiprazole is indicated for use asan adjunctive therapy to antidepressants for the treatment of majordepressive disorder (MDD). In some embodiments, brexpiprazole isindicated for the treatment of schizophrenia. Brexpiprazole may beadministered in a 0.25 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, and 4 mg dosageform. In some embodiments, brexpiprazole is administered once daily upto a total daily dose of 8 mg. For example, when brexpiprazole isindicated for use as an adjunctive therapy to antidepressants for thetreatment of major depressive disorder (MDD), the starting referencedose is 0.5 mg or 1 mg administered once daily (total daily referencedose is 0.5 mg or 1 mg). When brexpiprazole is indicated for use as anadjunctive therapy to antidepressants for the treatment of majordepressive disorder (MDD), the recommended reference dose is 2 mgadministered once daily (total daily reference dose is 2 mg). Whenbrexpiprazole is indicated for use as an adjunctive therapy toantidepressants for the treatment of major depressive disorder (MDD),the maximum dose is 3 mg administered once daily (total daily referencedose is 3 mg). For example, when brexpiprazole is indicated for treatingschizophrenia, the starting reference dose is 1 mg, administered oncedaily (total daily reference dose is 1 mg). When brexpiprazole isindicated for treating schizophrenia, the recommended reference dose is2-4 mg (e.g. 2 mg, 3 mg, or 4 mg), administered once daily (total dailyreference dose is 2-4 mg). When brexpiprazole is indicated for treatingschizophrenia, the maximum dose is 4 mg, administered once daily (totaldaily reference dose is 4 mg). Thus, in various embodiments, the totaldaily reference dose of brexpiprazole may be, for example, 0.25 mg, 0.5mg, 0.75 mg, 1 mg, 1.25 mg, 1.5 mg, 1.75 mg, 2 mg, 2.25 mg, 2.5 mg, 2.75mg, 3 mg, 3.25 mg, 3.5 mg, 3.75 mg, 4 mg, 4.25 mg, 4.5 mg, 4.75 mg, 5mg, 5.25 mg, 5.5 mg, 5.75 mg, 6 mg, 6.25 mg, 6.5 mg, 6.75 mg, 7 mg, 7.25mg, 7.5 mg, 7.75 mg or 8 mg. In accordance with certain embodiments ofthe present disclosure, when the total daily reference dose ofbrexpiprazole is, for example, 8 mg, the patient will take a reducedtotal daily dose of brexpiprazole (either concomitantly withposaconazole or after a delay period after stopping posaconazole). Insome embodiments, the reduced total daily dose of brexpiprazole is 0.25mg, 0.5 mg, 0.75 mg, 1 mg, 1.25 mg, 1.5 mg, 1.75 mg, 2 mg, 2.25 mg, 2.5mg, 2.75 mg, 3 mg, 3.25 mg, 3.5 mg, 3.75 mg, 4 mg, 4.25 mg, 4.5 mg, 4.75mg, 5 mg, 5.25 mg, 5.5 mg, 5.75 mg, 6 mg, 6.25 mg, 6.5 mg, 6.75 mg, 7mg, 7.25 mg, 7.5 mg, or 7.75 mg. When the total daily reference dose ofbrexpiprazole is 6 mg, the reduced total daily dose of brexpiprazole is,for example, 0.25 mg, 0.5 mg, 0.75 mg, 1 mg, 1.25 mg, 1.5 mg, 1.75 mg, 2mg, 2.25 mg, 2.5 mg, 2.75 mg, 3 mg, 3.25 mg, 3.5 mg, 3.75 mg, 4 mg, 4.25mg, 4.5 mg, 4.75 mg, 5 mg, 5.25 mg, 5.5 mg, or 5.75 mg, including allintegers and ranges therebetween. When the total daily reference dose ofbrexpiprazole is 4 mg, the reduced total daily dose of brexpiprazole is,for example, 0.25 mg, 0.5 mg, 0.75 mg, 1 mg, 1.25 mg, 1.5 mg, 1.75 mg, 2mg, 2.25 mg, 2.5 mg, 2.75 mg, 3 mg, 3.25 mg, 3.5 mg, or 3.75 mg,including all integers and ranges therebetween. When the total dailyreference dose of brexpiprazole is 3 mg, the reduced total daily dose ofbrexpiprazole is, for example, 0.25 mg, 0.5 mg, 0.75 mg, 1 mg, 1.25 mg,1.5 mg, 1.75 mg, 2 mg, 2.25 mg, 2.5 mg, or 2.75 mg, including allintegers and ranges therebetween. When the total daily reference dose ofbrexpiprazole is 2 mg, the reduced total daily dose of brexpiprazole is,for example, 0.25 mg, 0.5 mg, 0.75 mg, 1 mg, 1.25 mg, 1.5 mg, or 1.75mg, including all integers and ranges therebetween. When the total dailyreference dose of brexpiprazole is 1 mg, the reduced total daily dose ofbrexpiprazole is, for example, 0.25 mg, 0.5 mg, or 0.75 mg, includingall integers and ranges therebetween. When the total daily referencedose of brexpiprazole is 0.75 mg, the reduced total daily dose ofbrexpiprazole is, for example, 0.25 mg or 0.5 mg, including all integersand ranges therebetween. When the total daily reference dose ofbrexpiprazole is 0.5 mg, the reduced total daily dose of brexpiprazoleis, for example, 0.125 or 0.25 mg, including all integers and rangestherebetween. When the total daily reference dose of brexpiprazole is0.25 mg, the reduced total daily dose of brexpiprazole is, for example,0.125 mg. Correspondingly, when the individual reference dose ofbrexpiprazole is 4 mg, the reduced individual reference dose ofbrexpiprazole is, for example, 0.25 mg, 0.5 mg, 0.75 mg, 1 mg, 1.25 mg,1.5 mg, 1.75 mg, 2 mg, 2.25 mg, 2.5 mg, 2.75 mg, 3 mg, 3.25 mg, 3.5 mg,or 3.75 mg, including all integers and ranges therebetween. When theindividual reference dose of brexpiprazole is 3 mg, the reducedindividual reference dose of brexpiprazole is, for example, 0.25 mg, 0.5mg, 0.75 mg, 1 mg, 1.25 mg, 1.5 mg, 1.75 mg, 2 mg, 2.25 mg, 2.5 mg, or2.75 mg, including all integers and ranges therebetween. When theindividual reference dose of brexpiprazole is 2 mg, the reducedindividual reference dose of brexpiprazole is, for example, 0.25 mg, 0.5mg, 0.75 mg, 1 mg, 1.25 mg, 1.5 mg, or 1.75 mg, including all integersand ranges therebetween. When the individual reference dose ofbrexpiprazole is 1 mg, the reduced individual reference dose ofbrexpiprazole is, for example, 0.25 mg, 0.5 mg, or 0.75 mg, includingall integers and ranges therebetween. When the individual reference doseof brexpiprazole is 0.75 mg, the reduced individual reference dose ofbrexpiprazole is, for example, 0.25 mg or 0.5 mg, including all integersand ranges therebetween. When the individual reference dose ofbrexpiprazole is 0.5 mg, the reduced individual reference dose ofbrexpiprazole is, for example 0.125 or 0.25 mg, including all integersand ranges therebetween. When the individual reference dose ofbrexpiprazole is 0.25 mg, the reduced individual reference dose ofbrexpiprazole is, for example, 0.125 mg.

In some embodiments, the CYP3A4 substrate drug is brigatinib. Thedisease or condition treated with brigatinib can include any disease orcondition described herein or for which brigatinib is indicated. Forexample, in some embodiments, brigatinib is indicated for the treatmentof patients with anaplastic lymphoma kinase (ALK)-positive metastaticnon-small cell lung cancer (NSCLC) who have progressed on or areintolerant to crizotinib. Brigatinib may be administered in a 30 mg or90 mg dosage form. In some embodiments, brigatinib is administered oncedaily up to a total daily dose of 180 mg. For example, when brigatinibis indicated for the treatment of patients with anaplastic lymphomakinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) whohave progressed on or are intolerant to crizotinib, the reference doseis 90 mg, administered once daily for the first 7 days and if tolerated,increased to 180 mg once daily (total daily reference dose is 90 mg or180 mg). Thus, in various embodiments, the total daily reference dose ofbrigatinib may be, for example, 15 mg, 30 mg, 45 mg, 60 mg, 75 mg, 90mg, 105 mg, 120 mg, 135 mg, 150 mg, 165 mg, or 180 mg. In accordancewith certain embodiments of the present disclosure, when the total dailyreference dose of brigatinib is, for example, 180 mg, the patient willtake a reduced total daily dose of brigatinib (either concomitantly withposaconazole or after a delay period after stopping posaconazole). Insome embodiments, the reduced total daily dose of brigatinib is, forexample, 15 mg, 30 mg, 45 mg, 60 mg, 75 mg, 90 mg, 105 mg, 120 mg, 135mg, 150 mg, or 165 mg, including all integers and ranges therebetween.When the total daily reference dose of brigatinib is 180 mg, the reducedtotal daily dose of brigatinib is, for example, 15 mg, 30 mg, 45 mg, 60mg, 75 mg, 90 mg, 105 mg, 120 mg, 135 mg, 150 mg, 165 mg, including allintegers and ranges therebetween. When the total daily reference dose ofbrigatinib is 120 mg, the reduced total daily dose of brigatinib is, forexample, 15 mg, 30 mg, 45 mg, 60 mg, 75 mg, 90 mg, or 105 mg, includingall integers and ranges therebetween. When the total daily referencedose of brigatinib is 90 mg, the reduced total daily dose of brigatinibis, for example, 15 mg, 30 mg, 45 mg, 60 mg, or 75 mg, including allintegers and ranges therebetween. When the total daily reference dose ofbrigatinib is 60 mg, the reduced total daily dose of brigatinib is, forexample, 15 mg, 30 mg, or 45 mg, including all integers and rangestherebetween. When the total daily reference dose of brigatinib is 30mg, the reduced total daily dose of brigatinib is, for example, 7.5 mgor 15 mg, including all integers and ranges therebetween.Correspondingly, when the individual reference dose of brigatinib is 90mg, the reduced individual reference dose of brigatinib is, for example,15 mg, 30 mg, 45 mg, 60 mg, 75 mg, including all integers and rangestherebetween. When the individual reference dose of brigatinib is 30 mg,the reduced individual reference dose of brigatinib is, for example, 7.5mg or 15 mg, including all integers and ranges therebetween.

In some embodiments, the CYP3A4 substrate drug is cabazitaxel. Thedisease or condition treated with cabazitaxel can include any disease orcondition described herein or for which cabazitaxel is indicated. Forexample, in some embodiments, cabazitaxel is indicated in combinationwith prednisone for treatment of patients with metastaticcastration-resistant prostate cancer previously treated with adocetaxel-containing treatment regimen. Cabazitaxel may be administeredvia injection in a 15 mg/m², 20 mg/m², or a 25 mg/m² dosage form (soldas a single dose vial of 60 mg/1.5 mL). In some embodiments, cabazitaxelis administered once every three weeks corresponding to a total dose ofup to 25 mg/m² every three weeks. For example, when cabazitaxel isindicated for in combination with prednisone for treatment of patientswith metastatic castration-resistant prostate cancer previously treatedwith a docetaxel-containing treatment regimen, the reference dose is 20mg/m², administered once every 3 weeks (total reference dose is 20 mg/m²every 3 weeks). Thus, in various embodiments, the total reference doseof cabazitaxel may be, for example, 2.5 mg/m² every 3 weeks, 5 mg/m²every 3 weeks, 7.5 mg/m² every 3 weeks, 10 mg/m² every 3 weeks, 12.5mg/m² every 3 weeks, 15 mg/m² every 3 weeks, 17.5 mg/m² every 3 weeks,20 mg/m² every 3 weeks, 22.5 mg/m² every 3 weeks, or 25 mg/m² every 3weeks. In accordance with certain embodiments of the present disclosure,when the total reference dose of cabazitaxel is, for example, 25 mg/m²every 3 weeks, the patient will take a reduced total dose of cabazitaxel(either concomitantly with posaconazole or after a delay period afterstopping posaconazole). In some embodiments, the reduced total dose ofcabazitaxel is, for example, 2.5 mg/m² every 3 weeks, 5 mg/m² every 3weeks, 7.5 mg/m² every 3 weeks, 10 mg/m² every 3 weeks, 12.5 mg/m² every3 weeks, 15 mg/m² every 3 weeks, 17.5 mg/m² every 3 weeks, 20 mg/m²every 3 weeks, or 22.5 mg/m² every 3 weeks, including all integers andranges therebetween. When the total daily reference dose of cabazitaxelis 25 mg/m² every 3 weeks, the reduced total daily dose of cabazitaxelis, for example, 2.5 mg/m² every 3 weeks, 5 mg/m² every 3 weeks, 7.5mg/m² every 3 weeks, 10 mg/m² every 3 weeks, 12.5 mg/m² every 3 weeks,15 mg/m² every 3 weeks, 17.5 mg/m² every 3 weeks, 20 mg/m² every 3 weeksor 22.5 mg/m² every 3 weeks, including all integers and rangestherebetween. When the total daily reference dose of cabazitaxel is 20mg/m² every 3 weeks, the reduced total daily dose of cabazitaxel is, forexample, 2.5 mg/m² every 3 weeks, 5 mg/m² every 3 weeks, 7.5 mg/m² every3 weeks, 10 mg/m² every 3 weeks, 12.5 mg/m² every 3 weeks, 15 mg/m²every 3 weeks, or 17.5 mg/m² every 3 weeks, including all integers andranges therebetween. When the total daily reference dose of cabazitaxelis 15 mg/m² every 3 weeks, the reduced total daily dose of cabazitaxelis, for example, 2.5 mg/m² every 3 weeks, 5 mg/m² every 3 weeks, 7.5mg/m² every 3 weeks, 10 mg/m² every 3 weeks, or 12.5 mg/m² every 3weeks, including all integers and ranges therebetween.

In some embodiments, the CYP3A4 substrate drug is cannabidiol. Thedisease or condition treated with cannabidiol can include any disease orcondition described herein or for which cannabidiol is indicated. Forexample, in some embodiments, cannabidiol is indicated for for thetreatment of seizures associated with Lennox-Gastaut syndrome or Dravetsyndrome in patients 2 years of age and older. Cannabidiol may beadministered in a 100 mg/mL oral solution. In some embodiments,cannabidiol is administered once or twice daily up to a total daily doseof 20 mg/kg. For example, when cannabidiol is indicated for thetreatment of seizures associated with Lennox-Gastaut syndrome or Dravetsyndrome in patients 2 years of age and older, the starting referencedose is 2.5 mg/kg, administered twice daily (total daily reference doseis 5 mg/kg). After one week, the reference dose may be increased to 5mg/kg, administered twice daily (total daily reference dose is 10mg/kg). Based on individual clinical response and tolerability,cannabidiol may be increased to a maximum reference dose of 210 mg/kg,administered twice daily (total daily reference dose is 20 mg/kg). Thus,in various embodiments, the total daily reference dose of cannabidiolmay be, for example, 1 mg/kg, 2 mg/kg, 3 mg/kg, 4 mg/kg, 5 mg/kg, 6mg/kg, 7 mg/kg, 8 mg/kg, 9 mg/kg, 10 mg/kg, 11 mg/kg, 12 mg/kg, 13mg/kg, 14 mg/kg, 15 mg/kg, 16 mg/kg, 17 mg/kg, 18 mg/kg, 19 mg/kg, or 20mg/kg. In accordance with certain embodiments of the present disclosure,when the total daily reference dose of cannabidiol is, for example, 20mg/kg, the patient will take a reduced total daily dose of cannabidiol(either concomitantly with posaconazole or after a delay period afterstopping posaconazole). In some embodiments, the reduced total dailydose of cannabidiol is, for example, 1 mg/kg, 2 mg/kg, 3 mg/kg, 4 mg/kg,5 mg/kg, 6 mg/kg, 7 mg/kg, 8 mg/kg, 9 mg/kg, 10 mg/kg, 11 mg/kg, 12mg/kg, 13 mg/kg, 14 mg/kg, 15 mg/kg, 16 mg/kg, 17 mg/kg, 18 mg/kg, or 19mg/kg, including all integers and ranges therebetween. When the totaldaily reference dose of cannabidiol is 20 mg/kg, the reduced total dailydose of cannabidiol is, for example, 1 mg/kg, 2 mg/kg, 3 mg/kg, 4 mg/kg,5 mg/kg, 6 mg/kg, 7 mg/kg, 8 mg/kg, 9 mg/kg, 10 mg/kg, 11 mg/kg, 12mg/kg, 13 mg/kg, 14 mg/kg, 15 mg/kg, 16 mg/kg, 17 mg/kg, 18 mg/kg, or 19mg/kg, including all integers and ranges therebetween. When the totaldaily reference dose of cannabidiol is 10 mg/kg, the reduced total dailydose of cannabidiol is, for example, 1 mg/kg, 2 mg/kg, 3 mg/kg, 4 mg/kg,5 mg/kg, 6 mg/kg, 7 mg/kg, 8 mg/kg, or 9 mg/kg, including all integersand ranges therebetween. When the total daily reference dose ofcannabidiol is 5 mg/kg, the reduced total daily dose of cannabidiol is,for example, 1 mg/kg, 2 mg/kg, 3 mg/kg, or 4 mg/kg, including allintegers and ranges therebetween.

In some embodiments, the CYP3A4 substrate drug is cariprazine. Thedisease or condition treated with cariprazine can include any disease orcondition described herein or for which cariprazine is indicated. Forexample, in some embodiments, cariprazine is indicated for the treatmentof schizophrenia in adults. In some embodiments, cariprazine isindicated for acute treatment of manic or mixed episodes associated withbipolar I disorder in adults. Cariprazine may be administered in a 1.5mg, 3 mg, 4.5 mg, or 6 mg dosage form. In some embodiments, cariprazineis administered once daily up to a total daily dose of 6 mg. Forexample, when cariprazine is indicated for the treatment ofschizophrenia, the starting reference dose is 1.5 mg, administered oncedaily (total daily reference dose is 1.5 mg). When cariprazine isindicated for the treatment of schizophrenia, the reference dose may beincreased to up to 6 mg, administered once daily (total daily referencedose is 6 mg). For example, when cariprazine is indicated for acutetreatment of manic or mixed episodes associated with bipolar I disorderin adults, the starting reference dose is 1.5 mg, administered oncedaily (total daily reference dose is 1.5 mg). When cariprazine isindicated for acute treatment of manic or mixed episodes associated withbipolar I disorder in adults, the reference dose may be increased to upto 6 mg, administered once daily (total daily reference dose is 6 mg).Thus, in various embodiments, the total daily reference dose ofcariprazine may be, for example 0.75 mg, 1.5 mg, 2.25 mg, 3 mg, 3.75 mg,4.5 mg, 5.25 mg, or 6 mg. In accordance with certain embodiments of thepresent disclosure, when the total daily reference dose of cariprazineis, for example, 6 mg, the patient will take a reduced total daily doseof cariprazine (either concomitantly with posaconazole or after a delayperiod after stopping posaconazole). In some embodiments, the reducedtotal daily dose of cariprazine is, for example, 0.75 mg, 1.5 mg, 2.25mg, 3 mg, 3.75 mg, 4.5 mg, or 5.25 mg, including all integers and rangestherebetween. When the total daily reference dose of cariprazine is 6mg, the reduced total daily dose of cariprazine is, for example, 0.75mg, 1.5 mg, 2.25 mg, 3 mg, 3.75 mg, 4.5 mg, or 5.25 mg, including allintegers and ranges therebetween. When the total daily reference dose ofcariprazine is 4.5 mg, the reduced total daily dose of cariprazine is,for example, 0.75 mg, 1.5 mg, 2.25 mg, 3 mg, or 3.75 mg, including allintegers and ranges therebetween. When the total daily reference dose ofcariprazine is 3 mg, the reduced total daily dose of cariprazine is, forexample, 0.75 mg, 1.5 mg, 2.25 mg, or 3 mg, including all integers andranges therebetween. When the total daily reference dose of cariprazineis 1.5 mg, the reduced total daily dose of cariprazine is, for example,0.75 mg. Correspondingly, when the individual reference dose ofcariprazine is 6 mg, the reduced individual reference dose ofcariprazine is, for example, 0.75 mg, 1.5 mg, 2.25 mg, 3 mg, 3.75 mg,4.5 mg, or 5.25 mg, including all integers and ranges therebetween. Whenthe individual reference dose of cariprazine is 4.5 mg, the reducedindividual reference dose of cariprazine is, for example, 0.75 mg, 1.5mg, 2.25 mg, 3 mg, or 3.75 mg, including all integers and rangestherebetween. When the individual reference dose of cariprazine is 3 mg,the reduced individual reference dose of cariprazine is, for example,0.75 mg, 1.5 mg, or 2.25 mg, including all integers and rangestherebetween. When the individual reference dose of cariprazine is 1.5mg, the reduced individual reference dose of cariprazine is, forexample, 0.75 mg.

In some embodiments, the CYP3A4 substrate drug is cobimetinib. Thedisease or condition treated with cobimetinib can include any disease orcondition described herein or for which cobimetinib is indicated. Forexample, in some embodiments, cobimetinib is indicated for the treatmentof patients with unresectable or metastatic melanoma with a BRAF V600Eor V600K mutation, in combination with vemurafenib. Cobimetinib may beadministered in a 20 mg dosage form. In some embodiments, cobimetinib isadministered once daily up to a total daily dose of 60 mg. For example,when cobimetinib is indicated for the treatment of patients withunresectable or metastatic melanoma with a BRAF V600E or V600K mutation,in combination with vemurafenib, the reference dose is 60 mg,administered once daily (total daily reference dose is 60 mg). Thus, invarious embodiments, the total daily reference dose of cobimetinib maybe, for example, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, or 60 mg. Inaccordance with certain embodiments of the present disclosure, when thetotal daily reference dose of cobimetinib is, for example, 60 mg, thepatient will take a reduced total daily dose of cobimetinib (eitherconcomitantly with posaconazole or after a delay period after stoppingposaconazole). In some embodiments, the reduced total daily dose ofcobimetinib is, for example, 10 mg, 20 mg, 30 mg, 40 mg, or 50 mg,including all integers and ranges therebetween. When the total dailyreference dose of cobimetinib is 60 mg, the reduced total daily dose ofcobimetinib is, for example, 10 mg, 20 mg, 30 mg, 40 mg, or 50 mg,including all integers and ranges therebetween. Correspondingly, whenthe individual reference dose of cobimetinib is 20 mg, the reducedindividual reference dose of cobimetinib is, for example, 10 mg.

In some embodiments, the CYP3A4 substrate drug is copanlisib. Thedisease or condition treated with copanlisib can include any disease orcondition described herein or for which copanlisib is indicated. Forexample, in some embodiments, copanlisib is indicated for the treatmentof adult patients with relapsed follicular lymphoma (FL) who havereceived at least two prior systemic therapies. Copanlisib may beadministered in a one-hour intravenous infusion as 30 mg, 45 mg, or 60mg on days 1, 8 and 15 of a 28-day cycle dosage form. Thus, in someembodiments, copanlisib is administered on days 1, 8 and 15 of a 28-daycycle (three weeks on and one week off) up to a total dose of 180 mg/28days. For example, when copanlisib is indicated for the treatment ofadult patients with relapsed follicular lymphoma (FL) who have receivedat least two prior systemic therapies, the reference dose is 180 mg/28days, administered on days 1, 8 and 15 of a 28-day cycle (three weeks onand one week off) (total reference dose is 180 mg/28 days). Thus, invarious embodiments, the total daily reference dose of copanlisib maybe, for example, 90 mg/28 days, 135 mg/28 days, or 180 mg/28 days. Inaccordance with certain embodiments of the present disclosure, when thetotal daily reference dose of copanlisib is, for example, 180 mg/28days, the patient will take a reduced total daily dose of copanlisib(either concomitantly with posaconazole or after a delay period afterstopping posaconazole). In some embodiments, the reduced total dailydose of copanlisib is, for example, 10 mg/28 days, 20 mg/28 days, 30mg/28 days, 40 mg/28 days, 50 mg/28 days, 60 mg/28 days, 70 mg/28 days,80 mg/28 days, 90 mg/28 days, 100 mg/28 days, 110 mg/28 days, 120 mg/28days, 130 mg/28 days, 140 mg/28 days, 150 mg/28 days, 160 mg/28 days, or170 mg/28 days, including all integers and ranges therebetween. When thetotal daily reference dose of copanlisib is 135 mg/28 days, the reducedtotal daily dose of copanlisib is, for example, 10 mg/28 days, 20 mg/28days, 30 mg/28 days, 40 mg/28 days, 50 mg/28 days, 60 mg/28 days, 70mg/28 days, 80 mg/28 days, 90 mg/28 days, 100 mg/28 days, 110 mg/28days, or 120 mg/28 days, including all integers and ranges therebetween.When the total daily reference dose of copanlisib is 90 mg/28 days, thereduced total daily dose of copanlisib is, for example, 10 mg/28 days,20 mg/28 days, 30 mg/28 days, 40 mg/28 days, 50 mg/28 days, 60 mg/28days, 70 mg/28 days, or 80 mg/28 days, including all integers and rangestherebetween. Correspondingly, when the individual reference dose ofcopanlisib is 60 mg, the reduced individual reference dose of copanlisibis, for example, 10 mg, 20 mg, 30 mg, 40 mg, or 50 mg, including allintegers and ranges therebetween. When the individual reference dose ofcopanlisib is 45 mg, the reduced individual reference dose of copanlisibis, for example, 10 mg, 20 mg, 30 mg, or 40 mg, including all integersand ranges therebetween. When the individual reference dose ofcopanlisib is 30 mg, the reduced individual reference dose of copanlisibis, for example, 10 mg or 20 mg, including all integers and rangestherebetween.

In some embodiments, the CYP3A4 substrate drug is crizotinib. Thedisease or condition treated with crizotinib can include any disease orcondition described herein or for which crizotinib is indicated. Forexample, in some embodiments, crizotinib is indicated for the treatmentof patients with metastatic non-small cell lung cancer (NSCLC) whosetumors are anaplastic lymphoma kinase (ALK) or ROS1-positive as detectedby an FDA-approved test. Crizotinib may be administered in a 250 mg or200 mg dosage form. In some embodiments, crizotinib is administered oncedaily up to a total daily dose of 250 mg. In some embodiments,crizotinib is administered twice daily up to a total daily dose of 500mg. For example, when crizotinib is indicated for the treatment ofpatients with metastatic non-small cell lung cancer (NSCLC) whose tumorsare anaplastic lymphoma kinase (ALK) or ROS1-positive as detected by anFDA-approved test, the reference dose is 250 mg, administered twicedaily (total daily reference dose is 500 mg). In some embodiments, thepatient has severe renal impairment (creatinine clearance <30 mL/min)not requiring dialysis and is administered 250 mg once daily. Thus, invarious embodiments, the total daily reference dose of crizotinib maybe, for example, 100 mg, 125 mg, 200 mg, 250 mg, 300 mg, 375 mg, 400 mg,or 500 mg. In accordance with certain embodiments of the presentdisclosure, when the total daily reference dose of crizotinib is, forexample, 500 mg, the patient will take a reduced total daily dose ofcrizotinib (either concomitantly with posaconazole or after a delayperiod after stopping posaconazole). In some embodiments, the reducedtotal daily dose of crizotinib is, for example, 100 mg, 125 mg, 200 mg,250 mg, 300 mg, 375 mg, or 400 mg, including all integers and rangestherebetween. When the total daily reference dose of crizotinib is 500mg, the reduced total daily dose of crizotinib is, for example, 100 mg,125 mg, 200 mg, 250 mg, 300 mg, 375 mg, or 400 mg, including allintegers and ranges therebetween. When the total daily reference dose ofcrizotinib is 200 mg, the reduced total daily dose of crizotinib is, forexample, 100 mg or 125 mg, including all integers and rangestherebetween. Correspondingly, when the individual reference dose ofcrizotinib is 250 mg, the reduced individual reference dose ofcrizotinib is, for example, 100 mg, 125 mg, or 200 mg, including allintegers and ranges therebetween. When the individual reference dose ofcrizotinib is 200 mg, the reduced individual reference dose ofcrizotinib is, for example, 100 mg or 125 mg, including all integers andranges therebetween.

In some embodiments, the CYP3A4 substrate drug is dabrafenib. Thedisease or condition treated with dabrafenib can include any disease orcondition described herein or for which dabrafenib is indicated. Forexample, in some embodiments, dabrafenib is indicated as a single agentfor the treatment of patients with unresectable or metastatic melanomawith BRAF V600E mutation as detected by an FDA-approved test. In someembodiments, dabrafenib is indicated in combination with trametinib, forthe treatment of patients with unresectable or metastatic melanoma withBRAF V600E or V600K mutations as detected by an FDA-approved test. Insome embodiments, dabrafenib is indicated in combination withtrametinib, for the adjuvant treatment of patients with melanoma withBRAF V600E or V600K mutations, as detected by an FDA-approved test, andinvolvement of lymph node(s), following complete resection. In someembodiments, dabrafenib is indicated in combination with trametinib, forthe treatment of patients with metastatic non-small cell lung cancer(NSCLC) with BRAF V600E mutation as detected by an FDA-approved test. Insome embodiments, dabrafenib is indicated in combination withtrametinib, for the treatment of patients with locally advanced ormetastatic anaplastic thyroid cancer (ATC) with BRAF V600E mutation andwith no satisfactory locoregional treatment options. Dabrafenib may beadministered in a 50 mg or 75 mg dosage form. In some embodiments,dabrafenib is administered twice daily up to a total daily dose of 300mg. In some embodiments, dabrafenib is administered 150 mg orally twicedaily (total daily reference dose is 300 mg). For example, whendabrafenib is indicated for the treatment of patients with unresectableor metastatic melanoma with BRAF V600E mutation as detected by anFDA-approved test, the reference dose is 150 mg, administered twicedaily (total daily reference dose is 300 mg). When dabrafenib isindicated in combination with trametinib, for the treatment of patientswith unresectable or metastatic melanoma with BRAF V600E or V600Kmutations as detected by an FDA-approved test, the reference dose is 150mg, administered twice daily (total daily reference dose is 300 mg).When dabrafenib is indicated in combination with trametinib, for thetreatment of patients with metastatic non-small cell lung cancer (NSCLC)with BRAF V600E mutation as detected by an FDA-approved test, thereference dose is 150 mg, administered twice daily (total dailyreference dose is 300 mg). When dabrafenib is indicated in combinationwith trametinib, for the treatment of patients with locally advanced ormetastatic anaplastic thyroid cancer (ATC) with BRAF V600E mutation andwith no satisfactory locoregional treatment options, the reference doseis 150 mg, administered twice daily (total daily reference dose is 300mg). Thus, in various embodiments, the total daily reference dose ofdabrafenib may be, for example, 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, or 300 mg. In accordancewith certain embodiments of the present disclosure, when the total dailyreference dose of dabrafenib is, for example, 300 mg, the patient willtake a reduced total daily dose of dabrafenib (either concomitantly withposaconazole or after a delay period after stopping posaconazole). Insome embodiments, the reduced total daily dose of dabrafenib may be, forexample, 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg,225 mg, 250 mg or 275 mg, including all the integers and ranges that lietherebetween. When the total daily reference dose of dabrafenib is 275mg, the reduced total daily dose of dabrafenib may be, for example, 25mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg or 250mg, including all the integers and ranges that lie therebetween. Whenthe total daily reference dose of dabrafenib is 250 mg, the reducedtotal daily dose of dabrafenib may be, for example, 25 mg, 50 mg, 75 mg,100 mg, 125 mg, 150 mg, 175 mg, 200 mg or 225 mg, including all theintegers and ranges that lie therebetween. When the total dailyreference dose of dabrafenib is 225 mg, the reduced total daily dose ofdabrafenib may be, for example, 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150mg, 175 mg, or 200 mg, including all the integers and ranges that lietherebetween. Correspondingly, when the individual reference dose ofdabrafenib is 150 mg, the reduced individual reference dose ofdabrafenib may be, for example, 25 mg, 50 mg, 75 mg, 100 mg or 125 mg,including all the integers and ranges that lie therebetween.

In some embodiments, the CYP3A4 substrate drug is daclatasvir. Thedisease or condition treated with daclatasvir can include any disease orcondition described herein or for which daclatasvir is indicated. Forexample, in some embodiments, daclatasvir is indicated for use withsofosbuvir for the treatment of chronic HCV genotype 1 or 3 infection.In some embodiments, daclatasvir is indicated for use with sofosbuvirand ribavirin, for the treatment of chronic HCV genotype 1 or 3infection. Daclatasvir may be administered in a 30 mg, 60 mg or 90 mgdosage form. In some embodiments, daclatasvir is administered once dailyup to a total daily dose of 90 mg. For example, when daclatasvir isindicated for use with sofosbuvir for the treatment of chronic HCVgenotype 1 or 3 infection, the reference dose is 60 mg, administeredorally once daily (total daily reference dose is 60 mg). Whendaclatasvir is indicated for use with sofosbuvir and ribavirin, for thetreatment of chronic HCV genotype 1 or 3 infection, the reference doseis 60 mg, administered orally once daily (total daily reference dose is60 mg). Thus, in various embodiments, the total daily reference dose ofdaclatasvir may be, for example, 2.5 mg, 5 mg, 10 mg, 15 mg, 30 mg, 45mg, 60 mg, 75 mg or 90 mg. In accordance with certain embodiments of thepresent disclosure, when the total daily reference dose of daclatasviris, for example, 90 mg, the patient will take a reduced total daily doseof daclatasvir (either concomitantly with posaconazole or after a delayperiod after stopping posaconazole). In some embodiments, the reducedtotal daily dose of daclatasvir may be, for example, 2.5 mg, 5 mg, 10mg, 15 mg, 30 mg, 45 mg, 60 mg or 75 mg, including all the integers andranges that lie therebetween. When the total daily reference dose ofdaclatasvir is 60 mg, the reduced total daily dose of daclatasvir maybe, for example, 2.5 mg, 5 mg, 10 mg, 15 mg, 30 mg, or 45 mg, includingall the integers and ranges that lie therebetween. When the total dailyreference dose of daclatasvir is 30 mg, the reduced total daily dose ofdaclatasvir may be, for example, 2.5 mg, 5 mg, 10 mg, 15 mg, 30 mg or 45mg, including all the integers and ranges that lie therebetween.Correspondingly, when the individual reference dose of daclatasvir is 30mg, the reduced individual reference dose of daclatasvir may be, forexample, 2.5 mg, 5 mg, 10 mg, 15 mg, including all the integers andranges that lie therebetween. When the individual reference dose ofdaclatasvir is 60 mg, the reduced individual reference dose ofdaclatasvir may be, for example, 2.5 mg, 5 mg, 10 mg, 15 mg, 30 mg or 45mg, including all the integers and ranges that lie therebetween. Whenthe individual reference dose of daclatasvir is 90 mg, the reducedindividual reference dose of daclatasvir may be, for example, 2.5 mg, 5mg, 10 mg, 15 mg, 30 mg, 45 mg, 60 mg or 75 mg, including all theintegers and ranges that lie therebetween.

In some embodiments, the CYP3A4 substrate drug is dapagliflozin andsaxagliptin. The disease or condition treated with dapagliflozin andsaxagliptin can include any disease or condition described herein or forwhich dapagliflozin and saxagliptin is indicated. For example, in someembodiments, dapagliflozin and saxagliptin is indicated as an adjunct todiet and exercise to improve glycemic control in adults with type 2diabetes mellitus (T2DM) who have inadequate control with dapagliflozinor who are already treated with dapagliflozin and saxagliptin.Dapagliflozin and saxagliptin may be administered in 10 mgdapagliflozin/5 mg saxagliptin dosage form. In some embodiments,dapagliflozin and saxagliptinis is administered once daily. Thus, invarious embodiments, the total daily reference dose of dapagliflozin inthe dapagliflozin/saxagliptin drug may be, for example, 2.5 mg, 5 mg,7.5 mg, 10 mg, 15 mg or 20 mg and the total daily reference dose ofsaxagliptin in the dapagliflozin/saxagliptin drug may be, for example, 1mg, 2 mg, 3 mg, 4 mg, 5 mg, 8 mg or 10 mg. In accordance with certainembodiments of the present disclosure, when the total daily referencedose of dapagliflozin and saxagliptin is, for example, 10 mgdapagliflozin/5 mg saxagliptin, the patient will take a reduced totaldaily dose of dapagliflozin and saxagliptin (either concomitantly withposaconazole or after a delay period after stopping posaconazole). Insome embodiments, the reduced total daily dose of dapagliflozin in thedapagliflozin/saxagliptin drug may be, for example, 2.5 mg, 5 mg, or 7.5mg, including all the integers and ranges that lie therebetween and thereduced total daily dose of saxagliptin in the dapagliflozin/saxagliptindrug may be, for example, 1 mg, 2 mg, 3 mg, or 4 mg, including all theintegers and ranges that lie therebetween. In some embodiments, when thetotal daily reference dose of dapagliflozin and saxagliptin is, forexample, 5 mg dapagliflozin/2.5 mg saxagliptin, the reduced total dailydose of dapagliflozin in the dapagliflozin/saxagliptin drug may be, forexample, 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, or 4.5 mg,including all the integers and ranges that lie therebetween; and thereduced total daily dose of saxagliptin in the dapagliflozin/saxagliptindrug may be, for example, 1 mg, 1.5 mg, or 2 mg, including all theintegers and ranges that lie therebetween.

In some embodiments, the CYP3A4 substrate drug is deflazacort. Thedisease or condition treated with deflazacort can include any disease orcondition described herein or for which deflazacort is indicated. Forexample, in some embodiments, deflazacort is indicated for the treatmentof Duchenne muscular dystrophy (DMD) in patients 5 years of age andolder. Deflazacort may be administered in a 6 mg, 18 mg, 30 mg, and 36mg dosage form. In some embodiments, the recommended once-daily dosageof deflazacort is approximately 0.9 mg/kg/day administered orally. Forexample, when deflazacort is indicated for the treatment of Duchennemuscular dystrophy (DMD) in patients 5 years of age and older, thereference dose is 6 mg, administered once daily (total daily referencedose is 6 mg). In some embodiments, when deflazacort is indicated forthe treatment of Duchenne muscular dystrophy (DMD) in patients 5 yearsof age and older, the reference dose is 18 mg, administered once daily(total daily reference dose is 18 mg). In some embodiments, whendeflazacort is indicated for the treatment of Duchenne musculardystrophy (DMD) in patients 5 years of age and older, the reference doseis 30 mg, administered once daily (total daily reference dose is 30 mg).In some embodiments, when deflazacort is indicated for the treatment ofDuchenne muscular dystrophy (DMD) in patients 5 years of age and older,the reference dose is 36 mg, administered once daily (total dailyreference dose is 36 mg). Thus, in various embodiments, the total dailyreference dose of deflazacort may be, for example, 3 mg, 6 mg, 9 mg, 15mg, 18 mg, 30 mg, or 36 mg. In accordance with certain embodiments ofthe present disclosure, when the total daily reference dose ofdeflazacort is, for example, 36 mg the patient will take a reduced totaldaily dose of deflazacort (either concomitantly with posaconazole orafter a delay period after stopping posaconazole). In some embodiments,the reduced total daily dose of deflazacort may be, for example, 3 mg, 6mg, 9 mg, 15 mg, 18 mg or 30 mg, including all the integers and rangesthat lie therebetween. When the total daily reference dose ofdeflazacort is 30 mg, the reduced total daily dose of deflazacort maybe, for example, 3 mg, 6 mg, 9 mg, 15 mg or 18 mg, including all theintegers and ranges that lie therebetween. When the total dailyreference dose of deflazacort is 18 mg, the reduced total daily dose ofdeflazacort may be, for example, 3 mg, 6 mg, 9 mg or 15 mg, includingall the integers and ranges that lie therebetween. When the total dailyreference dose of deflazacort is 6 mg, the reduced total daily dose ofdeflazacort may be, for example, 1 mg, 3 mg or 5 mg, including all theintegers and ranges that lie therebetween.

In some embodiments, the CYP3A4 substrate drug is duvelisib. The diseaseor condition treated with duvelisib can include any disease or conditiondescribed herein or for which duvelisib is indicated. For example, insome embodiments, duvelisib is indicated for the treatment of adultpatients with relapsed or refractory chronic lymphocytic leukemia (CLL)or small lymphocytic lymphoma (SLL) after at least two prior therapies.In some embodiments, duvelisib is indicated for the treatment of adultpatients with relapsed or refractory follicular lymphoma (FL) after atleast two prior systemic therapies. Duvelisib may be administered in a15 mg or 25 mg dosage form. In some embodiments, duvelisib isadministered orally twice daily. For example, when duvelisib isindicated for the treatment of adult patients with relapsed orrefractory chronic lymphocytic leukemia (CLL) or small lymphocyticlymphoma (SLL) after at least two prior therapies, the reference dose is25 mg administered twice daily (total daily reference dose is 50 mg).For example, when duvelisib is indicated for the treatment of adultpatients with relapsed or refractory follicular lymphoma (FL) after atleast two prior systemic therapies, the reference dose is 25 mgadministered twice daily (total daily reference dose is 50 mg). Thus, invarious embodiments, the total daily reference dose of duvelisib may be,for example, 2.5 mg 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 40 mg or 50mg. In accordance with certain embodiments of the present disclosure,when the total daily reference dose of duvelisib is, for example, 50 mg,the patient will take a reduced total daily dose of duvelisib (eitherconcomitantly with posaconazole or after a delay period after stoppingposaconazole). In some embodiments, the reduced total daily dose ofduvelisib may be, for example, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg or 40mg, including all the integers and ranges that lie therebetween. Whenthe total daily reference dose of duvelisib is 40 mg, the reduced totaldaily dose of duvelisib may be, for example, 10 mg, 15 mg, 20 mg, 25 mgor 30 mg, including all the integers and ranges that lie therebetween.When the total daily reference dose of duvelisib is 30 mg, the reducedtotal daily dose of duvelisib may be, for example, 10 mg, 15 mg, 20 mgor 25 mg, including all the integers and ranges that lie therebetween.Correspondingly, when the individual reference dose of duvelisib is 15mg g, the reduced individual reference dose of duvelisib may be, forexample, 2.5 mg 5 mg or 10 mg, including all the integers and rangesthat lie therebetween. When the individual reference dose of duvelisibis 25 mg, the reduced individual reference dose of duvelisib may be, forexample, 2.5 mg 5 mg, 10 mg, 15 mg, 20 mg, including all the integersand ranges that lie therebetween.

In some embodiments, the CYP3A4 substrate drug is elbasvir andgrazoprevir. The disease or condition treated with elbasvir andgrazoprevir can include any disease or condition described herein or forwhich elbasvir and grazoprevir is indicated. For example, in someembodiments, elbasvir and grazoprevir is indicated for treatment ofchronic HCV genotype 1 or 4 infection in adults. In some embodiments,elbasvir and grazoprevir is indicated for use with ribavirin in certainpatient populations. Elbasvir and grazoprevir may be administered in a50 mg elbasvir and 100 mg grazoprevir dosage form. In some embodiments,elbasvir and grazoprevir is administered once daily. For example, whenelbasvir and grazoprevir is indicated for treatment of chronic HCVgenotype 1 or 4 infection in adults, the reference dose is 50 mgelbasvir and 100 mg grazoprevir administered once daily (total dailyreference dose is 50 mg elbasvir and 100 mg grazoprevir). For example,when elbasvir and grazoprevir is indicated for use with ribavirin incertain patient populations, the reference dose is 50 mg elbasvir and100 mg grazoprevir administered once daily (total daily reference doseis 50 mg elbasvir and 100 mg grazoprevir). Thus, in various embodiments,the total daily reference dose of elbasvir and grazoprevir may be, forexample, 5 mg elbasvir and 10 mg grazoprevir, 10 mg elbasvir and 25 mggrazoprevir, 25 mg elbasvir and 50 mg grazoprevir or 50 mg elbasvir and100 mg grazoprevir. In accordance with certain embodiments of thepresent disclosure, when the total daily reference dose of elbasvir andgrazoprevir is, for example, 50 mg elbasvir and 100 mg grazoprevir, thepatient will take a reduced total daily dose of elbasvir and grazoprevir(either concomitantly with posaconazole or after a delay period afterstopping posaconazole). In some embodiments, the reduced total dailydose of elbasvir in the elbasvir/grazoprevir drug may be, for example, 5mg, 10 mg, 20 mg, 30 mg, or 40 mg, including all the integers and rangesthat lie therebetween. In some embodiments, the reduced total daily doseof grazoprevir in the elbasvir/grazoprevir drug may be, for example, 10mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg or 90 mg, includingall the integers and ranges that lie therebetween. In some embodiments,when the total daily reference dose of elbasvir and grazoprevir is, forexample, 25 mg elbasvir and 50 mg grazoprevir, the reduced total dailydose of elbasvir may be, for example, 1 mg, 5 mg, 10 mg, 15 mg, or 20mg, including all the integers and ranges that lie therebetween; and thereduced total daily dose of grazoprevir may be, for example, 10 mg, 20mg, 30 mg, or 40 mg.

In some embodiments, the CYP3A4 substrate drug is encorafenib. Thedisease or condition treated with encorafenib can include any disease orcondition described herein or for which encorafenib is indicated. Forexample, in some embodiments, encorafenib is indicated, in combinationwith binimetinib, for the treatment of patients with unresectable ormetastatic melanoma with a BRAF V600E or V600K mutation, as detected byan FDA-approved test. Encorafenib may be administered in a 50 mg and 75mg dosage form. In some embodiments, when encorafenib is indicated, incombination with binimetinib, for the treatment of patients withunresectable or metastatic melanoma with a BRAF V600E or V600K mutation,as detected by an FDA-approved test, the reference dose is 450 mg ofencorafenib administered once daily (total daily reference dose is 450mg). Thus, in various embodiments, the total daily reference dose ofencorafenib may be, for example, 25 mg, 50 mg, 35 mg, 75 mg, 100 mg, 150mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, or 500 mg. Inaccordance with certain embodiments of the present disclosure, when thetotal daily reference dose of encorafenib is, for example, 450 mg, thepatient will take a reduced total daily dose of encorafenib (eitherconcomitantly with posaconazole or after a delay period after stoppingposaconazole). In some embodiments, the reduced total daily dose ofencorafenib may be, for example, 25 mg, 35 mg, 50 mg, 75 mg, 100 mg, 150mg, 200 mg, 250 mg, 300 mg, 350 mg, or 400 mg, including all integersand ranges therebetween. When the total daily reference dose ofencorafenib is 450 mg, the reduced total daily dose of encorafenib maybe, for example, 25 mg, 35 mg, 50 mg, 75 mg, 100 mg, 150 mg, 200 mg, 250mg, 300 mg, 350 mg, or 400 mg, including all integers and rangestherebetween. When the total daily reference dose of encorafenib is 400mg, the reduced total daily dose of encorafenib may be, for example, 25mg, 35 mg, 50 mg, 75 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg or 350mg, including all integers and ranges therebetween. When the total dailyreference dose of encorafenib is 350 mg, the reduced total daily dose ofencorafenib may be, for example, 25 mg, 35 mg, 50 mg, 75 mg, 100 mg, 150mg, 200 mg, 250 mg or 300 mg, including all integers and rangestherebetween. Correspondingly, when the individual reference dose ofencorafenib is 75 g, the reduced individual reference dose ofencorafenib may be, for example, 25 mg, 35 mg or 50 mg, including allintegers and ranges therebetween. When the individual reference dose ofencorafenib is 50 mg, the reduced individual reference dose ofencorafenib may be, for example, 10 mg, 25 mg or 35 mg, including allintegers and ranges therebetween.

In some embodiments, the CYP3A4 substrate drug is flibanserin. Thedisease or condition treated with flibanserin can include any disease orcondition described herein or for which flibanserin is indicated. Forexample, in some embodiments, flibanserin is indicated for the treatmentof premenopausal women with acquired, generalized hypoactive sexualdesire disorder (HSDD) as characterized by low sexual desire that causesmarked distress or interpersonal difficulty and is not due to aco-existing medical or psychiatric condition; problems within therelationship; or the effects of a medication or other drug substance.Flibanserin may be administered in a 100 mg dosage form. In someembodiments, flibanserin is administered once daily. For example, whenflibanserin is indicated for the treatment of premenopausal women withacquired, generalized hypoactive sexual desire disorder (HSDD) ascharacterized by low sexual desire that causes marked distress orinterpersonal difficulty and is not due to a co-existing medical orpsychiatric condition; problems within the relationship; or the effectsof a medication or other drug substance, the reference dose is 100 mg,administered once daily (total daily reference dose is 100 mg). Invarious embodiments, the total daily reference dose of flibanserin maybe, for example, 25 mg, 50 mg, 75 mg, or 100 mg. In accordance withcertain embodiments of the present disclosure, when the total dailyreference dose of flibanserin is, for example, 100 mg, the patient willtake a reduced total daily dose of flibanserin (either concomitantlywith posaconazole or after a delay period after stopping posaconazole).In some embodiments, the reduced total daily dose of flibanserin may be,for example, 25 mg, 50 mg, or 75 mg, including all integers and rangestherebetween. When the total daily reference dose of flibanserin is 100mg, the reduced total daily dose of flibanserin may be, for example, 25mg, 50 mg, or 75 mg, including all integers and ranges therebetween.Correspondingly, when the individual reference dose of flibanserin is100 mg, the reduced individual reference dose of flibanserin may be, forexample, 25 mg, 50 mg, or 75 mg, including all integers and rangestherebetween.

In some embodiments, the CYP3A4 substrate drug is fluticasone propionateand salmeterol. The disease or condition treated with fluticasonepropionate and salmeterol can include any disease or condition describedherein or for which fluticasone propionate and salmeterol is indicated.For example, in some embodiments, fluticasone propionate and salmeterolis indicated for treatment of asthma in patients aged 12 years or older.Fluticasone propionate may be administered in a 45, 115, or 230 mcgdosage form, in combination with salmeterol in a 21 mcg dosage form, asan aerosol formulation for oral inhalation. In some embodiments,fluticasone propionate and salmeterol is administered twice daily. Forexample, in some embodiments, when fluticasone propionate and salmeterolis indicated for treatment of asthma in patients aged 12 years or older,the reference dose is 45 mcg fluticasone propionate and 21 mcgsalmeterol, administered twice daily (total daily reference dose is 90mcg fluticasone propionate and 42 mcg salmeterol). In some embodiments,when fluticasone propionate and salmeterol is indicated for treatment ofasthma in patients aged 12 years or older, the reference dose is 115 mcgfluticasone propionate and 21 mcg salmeterol, administered twice daily(total daily reference dose is 230 mcg fluticasone propionate and 42 mcgsalmeterol). In some embodiments, when fluticasone propionate andsalmeterol is indicated for treatment of asthma in patients aged 12years or older, the reference dose is 230 mcg fluticasone propionate and21 mcg salmeterol, administered twice daily (total daily reference doseis 460 mcg fluticasone propionate and 42 mcg salmeterol). Thus, invarious embodiments, the total daily reference dose of fluticasonepropionate may be, for example, 10 mcg, 20 mcg, 40 mcg, 45 mcg, 60 mcg,90 mcg, 115 mcg, 230 mcg, 300 mcg, 400 mcg or 460 mcg and the totaldaily reference dose of salmeterol may be, for example, 5 mcg, 10 mcg,15 mcg, 21 mcg, 42 mcg, 63 mcg, or 84 mcg. In accordance with certainembodiments of the present disclosure, when the total daily referencedose of fluticasone propionate is, for example, 460 mcg, and the totaldaily reference dose of salmeterol is 42 mcg, the patient will take areduced total daily dose of fluticasone propionate and salmeterol(either concomitantly with posaconazole or after a delay period afterstopping posaconazole). In some embodiments, the reduced total dailydose of fluticasone propionate may be, for example, 10 mcg, 20 mcg, 40mcg, 45 mcg, 60 mcg, 90 mcg, 115 mcg, 230 mcg, 300 mcg, or 400 mcg,including all integers and ranges therebetween; and the reduced totaldaily dose of salmeterol may be, for example, 5 mcg, 10 mcg, 15 mcg, 21mcg, 30 mcg, or 35 mcg, including all integers and ranges therebetween.When the total daily reference dose of fluticasone propionate is 230 mcgand the total daily reference dose of salmeterol is 42 mcg, the reducedtotal daily dose of fluticasone propionate may be, for example, 10 mcg,20 mcg, 40 mcg, 45 mcg, 60 mcg, 90 mcg, or 115 mcg; and the reducedtotal daily dose of salmeterol may be, for example, 5 mcg, 10 mcg, 15mcg or 21 mcg, 30 mcg, or 35 mcg, including all integers and rangestherebetween. When the total daily reference dose of fluticasonepropionate is 90 mcg and the total daily dose of salmeterol is 42 mcg,the reduced total daily dose of fluticasone propionate may be, forexample, 10 mcg, 20 mcg, 40 mcg, 45 mcg, or 60 mcg, including allintegers and ranges therebetween and the reduced total daily dose ofsalmeterol is 5 mcg, 10 mcg, or 15 mcg, 30 mcg, or 35 mcg, including allintegers and ranges therebetween. Correspondingly, when the individualreference dose of fluticasone propionate is 45 mcg and the individualreference dose of salmeterol is 21 mcg, the reduced individual referencedose of fluticasone propionate may be, for example, 5 mcg, 10 mcg, 15mcg, 20 mcg, 30 mcg, or 40 mcg, including all integers and rangestherebetween and the reduced individual reference dose of salmeterol maybe, for example, 5 mcg, 10 mcg or 15 mcg, including all integers andranges therebetween. When the individual reference dose of fluticasonepropionate is 115 mcg and the individual reference dose of salmeterol is21 mcg, the reduced individual reference dose of fluticasone propionatemay be, for example, 100 mcg, 90 mcg, 45 mcg, 30 mcg, 20 mcg, 10 mcg or5 mcg, including all integers and ranges therebetween and the reducedindividual reference dose of salmeterol may be, for example, 5 mcg, 10mcg or 15 mcg, including all integers and ranges therebetween. When theindividual reference dose of fluticasone propionate is 230 mcg and theindividual reference dose of salmeterol is 21 mcg, the reducedindividual reference dose of fluticasone propionate may be, for example,5 mcg, 10 mcg, 20 mcg, 30 mcg, 45 mcg, 90 mcg, 100 mcg, 200 mcg,including all integers and ranges therebetween and the reducedindividual reference dose of salmeterol may be, for example, 5 mcg, 10mcg or 15 mcg, including all integers and ranges therebetween.

In some embodiments, the CYP3A4 substrate drug is ibrutinib. The diseaseor condition treated with ibrutinib can include any disease or conditiondescribed herein or for which ibrutinib is indicated. For example, insome embodiments, ibrutinib is indicated for the treatment of adultpatients with mantle cell lymphoma (MCL) who have received at least oneprior therapy. In some embodiments, ibrutinib is indicated for thetreatment of chronic lymphocytic leukemia (CLL)/Small lymphocyticlymphoma (SLL). In some embodiments, ibrutinib is indicated for thetreatment of chronic lymphocytic leukemia (CLL)/Small lymphocyticlymphoma (SLL) with 17p deletion. In some embodiments, ibrutinib isindicated for the treatment of waldenström's macroglobulinemia (WM). Insome embodiments, ibrutinib is indicated for the treatment of Marginalzone lymphoma (MZL) who require systemic therapy and have received atleast one prior anti-CD20-based therapy. In some embodiments, ibrutinibis indicated for the treatment of chronic graft versus host disease(cGVHD) after failure of one or more lines of systemic therapy.Ibrutinib may be administered as capsules in 70 mg or 140 mg dosageform; or as tablets in 140 mg, 280 mg, 420 mg, or 560 mg dosage forms.In some embodiments, ibrutinib is administered once daily. In someembodiments, when ibrutinib is indicated for the treatment of adultpatients with mantle cell lymphoma (MCL) who have received at least oneprior therapy, the reference dose 560 mg, administered once daily (totaldaily reference dose is 560 mg). In some embodiments, when ibrutinib isindicated for the treatment of Marginal zone lymphoma (MZL) who requiresystemic therapy and have received at least one prior anti-CD20-basedtherapy, the reference dose is 560 mg, administered once daily (totaldaily reference dose is 560 mg). In some embodiments, when ibrutinib isindicated for the treatment of chronic lymphocytic leukemia (CLL)/Smalllymphocytic lymphoma (SLL), the reference dose is 420 mg, administeredonce daily (total daily reference dose is 420 mg). In some embodiments,when ibrutinib is indicated for the treatment of waldenström'smacroglobulinemia (WM), the reference dose is 420 mg administered oncedaily (total daily reference dose is 420 mg). In some embodiments, whenibrutinib is indicated for the treatment of chronic graft versus hostdisease (cGVHD) after failure of one or more lines of systemic therapy,the reference dose is 420 mg, administered once daily (total dailyreference dose is 420 mg). Thus, in various embodiments, the total dailyreference dose of ibrutinib may be, for example, 25 mg, 50 mg, 70 mg,100 mg, 140 mg, 200 mg, 280 mg, 300 mg, 350 mg, 400 mg, 420 mg, 450 mg,500 mg or 550 mg or 560 mg. In accordance with certain embodiments ofthe present disclosure, when the total daily reference dose of ibrutinibis, for example, 560 mg, the patient will take a reduced total dailydose of ibrutinib (either concomitantly with posaconazole or after adelay period after stopping posaconazole). In some embodiments, thereduced total daily dose of ibrutinib may be, for example, 25 mg, 50 mg,70 mg, 100 mg, 140 mg, 200 mg, 280 mg, 300 mg, 350 mg, 400 mg, 420 mg,450 mg, 500 mg or 550 mg, including all integers and rangestherebetween. When the total daily reference dose of ibrutinib is 420mg, the reduced total daily dose of ibrutinib may be, for example, 25mg, 50 mg, 70 mg, 100 mg, 140 mg, 200 mg, 280 mg, 300 mg, 350 mg, or 400mg, including all integers and ranges therebetween. When the total dailyreference dose of ibrutinib is 280 mg, the reduced total daily dose ofibrutinib may be, for example, 25 mg, 50 mg, 70 mg, 100 mg, 140 mg, or200 mg, including all integers and ranges therebetween. When the totaldaily reference dose of ibrutinib is 140 mg, the reduced total dailydose of ibrutinib may be, for example, 25 mg, 50 mg, 70 mg, or 100 mg,including all integers and ranges therebetween. When the total dailyreference dose of ibrutinib is 70 mg, the reduced total daily dose ofibrutinib may be, for example, 25 mg or 50 mg, including all integersand ranges therebetween. Correspondingly, when the individual referencedose of ibrutinib is 70 mg, the reduced individual reference dose ofibrutinib may be, for example, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, or 60mg, including all integers and ranges therebetween. When the individualreference dose of ibrutinib is 140 mg, the reduced individual referencedose of ibrutinib may be, for example, 10 mg, 20 mg, 30 mg, 40 mg, 50mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, or 130 mg,including all integers and ranges therebetween. When the individualreference dose of ibrutinib is 280 mg, the reduced individual referencedose of ibrutinib may be, for example, 10 mg, 50 mg, 100 mg, 150 mg, 200mg, or 250 mg, including all integers and ranges therebetween. When theindividual reference dose of ibrutinib is 420 mg, the reduced individualreference dose of ibrutinib may be, for example, 50 mg, 100 mg, 150 mg,200 mg, 250 mg, 300 mg or 400 mg including all integers and rangestherebetween. When the individual reference dose of ibrutinib is 560 mg,the reduced individual reference dose of ibrutinib may be, for example,50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 400 mg, 420 mg, 450 mg,500 mg, or 550 mg, including all integers and ranges therebetween.

In some embodiments, the CYP3A4 substrate drug is ivabradine. Thedisease or condition treated with ivabradine can include any disease orcondition described herein or for which ivabradine is indicated. Forexample, in some embodiments, ivabradine is indicated to reduce the riskof hospitalization for worsening heart failure in patients with stable,symptomatic chronic heart failure with left ventricular ejectionfraction ≤35%, who are in sinus rhythm with resting heart rate ≥70 beatsper minute and either are on maximally tolerated doses of beta-blockersor have a contraindication to beta-blocker use. Ivabradine may beadministered in a 5 mg or 7.5 mg dosage form. In some embodiments,ivabradine is administered twice daily. In some embodiments, whenivabradine is indicated to reduce the risk of hospitalization forworsening heart failure in patients with stable, symptomatic chronicheart failure with left ventricular ejection fraction ≤35%, who are insinus rhythm with resting heart rate ≥70 beats per minute and either areon maximally tolerated doses of beta-blockers or have a contraindicationto beta-blocker use, the reference dose is 5 mg administered twice daily(total daily reference dose is 10 mg). In some embodiments, whenivabradine is indicated to reduce the risk of hospitalization forworsening heart failure in patients with stable, symptomatic chronicheart failure with left ventricular ejection fraction ≤35%, who are insinus rhythm with resting heart rate ≥70 beats per minute and either areon maximally tolerated doses of beta-blockers or have a contraindicationto beta-blocker use, the reference dose is 7.5 mg, administered twicedaily (total daily reference dose is 15 mg). In some embodiments, whenivabradine is indicated to reduce the risk of hospitalization forworsening heart failure in patients with stable, symptomatic chronicheart failure with left ventricular ejection fraction ≤35%, who are insinus rhythm with resting heart rate ≥70 beats per minute; either are onmaximally tolerated doses of beta-blockers or have a contraindication tobeta-blocker use and with conduction defects or in whom bradycardiacould lead to hemodynamic compromise, the reference dose is 2.5 mg,administered twice daily (total daily reference dose is 5 mg). Invarious embodiments, the total daily reference dose of ivabradine maybe, for example, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 10 mg, or 15 mg. Inaccordance with certain embodiments of the present disclosure, when thetotal daily reference dose of ivabradine is, for example, 15 mg, thepatient will take a reduced total daily dose of ivabradine (eitherconcomitantly with posaconazole or after a delay period after stoppingposaconazole). In some embodiments, the reduced total daily dose ofivabradine may be, for example, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg or 10 mg,including all integers and ranges therebetween. When the total dailyreference dose of ivabradine is 10 mg, the reduced total daily dose ofivabradine may be, for example, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7mg, 8 mg, 9 mg, including all integers and ranges therebetween. When thetotal daily reference dose of ivabradine is 5 mg, the reduced totaldaily dose of ivabradine may be, for example, 1 mg, 2 mg, 3 mg or 4 mg,including all integers and ranges therebetween. Correspondingly, whenthe individual reference dose of ivabradine is 7.5 g, the reducedindividual reference dose of ivabradine may be, for example, 1 mg, 2 mg,3 mg, 4 mg, 5 mg or 6 mg, including all integers and rangestherebetween. When the individual reference dose of ivabradine is 5 mg,the reduced individual reference dose of ivabradine may be, for example,1 mg, 2 mg, 3 mg, or 4 mg, including all integers and rangestherebetween. When the individual reference dose of ivabradine is 2.5mg, the reduced individual reference dose of ivabradine may be, forexample, 0.5 mg, 1 mg, 1.5 mg or 2 mg, including all integers and rangestherebetween.

In some embodiments, the CYP3A4 substrate drug is ivacaftor. The diseaseor condition treated with ivacaftor can include any disease or conditiondescribed herein or for which ivacaftor is indicated. For example, insome embodiments, ivacaftor is indicated for the treatment of cysticfibrosis (CF) in patients age 12 months and older who have one mutationin the CFTR gene that is responsive to ivacaftor based on clinicaland/or in vitro assay data. Ivacaftor may be administered as a tablet ina 150 mg dosage form or as oral granules in unit packets of 50 mg or 75mg. In some embodiments, ivacaftor is administered twice daily up to atotal daily dose of 300 mg to adults and pediatric patients age 6 yearsand older. In some embodiments, ivacaftor is administered twice daily upto a total daily dose of 100 mg to pediatric patients 12 months to lessthan 6 years of age and weighing 7 kg to less than 14 kg. In someembodiments, ivacaftor is administered twice daily up to a total dailydose of 150 mg to pediatric patients 12 months to less than 6 years ofage and 14 kg or greater. In various embodiments, the total dailyreference dose of ivacaftor may be, for example, 25 mg, 50 mg, 75 mg,100 mg, 125 mg, 150 mg, 200 mg, 250 mg or 300 mg. In accordance withcertain embodiments of the present disclosure, when the total dailyreference dose of ivacaftor is, for example, 300 mg, the patient willtake a reduced total daily dose of ivacaftor (either concomitantly withposaconazole or after a delay period after stopping posaconazole). Insome embodiments, the reduced total daily dose of ivacaftor may be, forexample, 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 200 mg, or 250 mg,including all integers and ranges therebetween. When the total dailyreference dose of ivacaftor is 300 mg, the reduced total daily dose ofivacaftor may be, for example, 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150mg, 200 mg, or 250 mg, including all integers and ranges therebetween.When the total daily reference dose of ivacaftor is 150 mg, the reducedtotal daily dose of ivacaftor may be, for example, 25 mg, 50 mg, 75 mg,100 mg, or 125 mg, including all integers and ranges therebetween. Whenthe total daily reference dose of ivacaftor is 100 mg, the reduced totaldaily dose of ivacaftor may be, for example, 25 mg, 50 mg, or 75 mg,including all integers and ranges therebetween. Correspondingly, whenthe individual reference dose of ivacaftor is 150 mg, the reducedindividual reference dose of ivacaftor may be, for example, 25 mg, 50mg, 75 mg, 100 mg, or 125 mg, including all integers and rangestherebetween. When the individual reference dose of ivacaftor is 75 mg,the reduced individual reference dose of ivacaftor may be, for example,5 mg, 10 mg, 15 mg, 20 mg, 25 mg or 50 mg, including all integers andranges therebetween. When the individual reference dose of ivacaftor is50 mg, the reduced individual reference dose of ivacaftor may be, forexample, 5 mg, 10 mg, 15 mg, 20 mg, or 25 mg, including all integers andranges therebetween.

In some embodiments, the CYP3A4 substrate drug is lumacaftor andivacaftor. The disease or condition treated with lumacaftor andivacaftor can include any disease or condition described herein or forwhich lumacaftor and ivacaftor is indicated. For example, in someembodiments, lumacaftor and ivacaftor is indicated for the treatment ofcystic fibrosis (CF) in patients age 2 years and older who arehomozygous for the F508del mutation in the CFTR gene. In someembodiments, lumacaftor and ivacaftor may be administered in the form oftablets containing a 100 mg lumacaftor and 125 mg ivacaftor; or 200 mglumacaftor and 125 mg ivacaftor. In some embodiments, lumacaftor andivacaftor may be administered as oral granules in unit-dose packets of100 mg lumacaftor and 125 mg ivacaftor; or 150 mg lumacaftor and 188 mgivacaftor. In some embodiments, lumacaftor and ivacaftor is administeredas one packet of granules containing 100 mg lumacaftor and 125 mgivacaftor twice daily (total daily reference dose is 200 mg lumacaftorand 250 mg ivacaftor) in pediatric patients of age 2 through 5 years andweighing less than 14 kg. In some embodiments, lumacaftor and ivacaftoris administered as one packet of granules containing 150 mg lumacaftorand 188 mg ivacaftor twice daily (total daily reference dose is 300 mglumacaftor and 376 mg ivacaftor) in pediatric patients of age 2 through5 years and weighing 14 kg or greater. In some embodiments, lumacaftorand ivacaftor is administered as two tablets each containing lumacaftor100 mg/ivacaftor 125 mg twice daily (total daily reference dose of 400mg lumacaftor and 500 mg ivacaftor) in pediatric patients of age 6through 11 years. In some embodiments, lumacaftor and ivacaftor isadministered as two tablets each containing lumacaftor 200 mg/ivacaftor125 mg twice daily up (total daily reference dose is 800 mg lumacaftorand 500 mg ivacaftor) in adults and pediatric patients of age 12 yearsand older. Thus, in various embodiments, the total daily reference doseof lumacaftor is 200 mg, 300 mg, 400 mg or 800 mg and the total dailyreference dose of ivacaftor is 250 mg, 376 mg or 500 mg. In accordancewith certain embodiments of the present disclosure, when the total dailyreference dose of lumacaftor is, for example, 800 mg, the patient willtake a reduced total daily dose of lumacaftor (either concomitantly withposaconazole or after a delay period after stopping posaconazole).Therefore, in some embodiments, the reduced total daily dose oflumacaftor in the lumacaftor/ivacaftor drug may be, for example, 50 mg,100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg or 700 mg, including allintegers and ranges therebetween. In some embodiments, when the totaldaily reference dose of lumacaftor is 400 mg, the reduced total dailydose of lumacaftor in the lumacaftor/ivacaftor drug may be, for example,50 mg, 100 mg, 200 mg or 300 mg, including all integers and rangestherebetween. In some embodiments, when the total daily reference doseof lumacaftor is 300 mg, the reduced total daily dose of lumacaftor inthe lumacaftor/ivacaftor drug may be, for example, 50 mg, 100 mg or 200mg, including all integers and ranges therebetween. Correspondingly, insome embodiments, when the individual reference dose of lumacaftor is100 mg then the reduced individual reference dose of lumacaftor in thelumacaftor/ivacaftor drug may be, for example, 10 mg, 25 mg, 50 mg or 75mg, including all integers and ranges therebetween. In some embodiments,when the individual reference dose of lumacaftor is 150 mg then thereduced individual reference dose of lumacaftor in thelumacaftor/ivacaftor drug may be, for example, 10 mg, 25 mg, 50 mg, 75mg, 100 mg or 125 mg, including all integers and ranges therebetween. Insome embodiments, when the individual reference dose of lumacaftor is188 mg then the reduced individual reference dose of lumacaftor in thelumacaftor/ivacaftor drug may be, for example, 10 mg, 25 mg, 50 mg, 75mg, 100 mg, 125 mg or 150 mg, including all integers and rangestherebetween. In some embodiments, when the total daily reference doseof ivacaftor is for example, 500 mg, the patient will take a reducedtotal daily dose of ivacaftor (either concomitantly with posaconazole orafter a delay period after stopping posaconazole). Thus, in someembodiments, the reduced total daily dose of ivacaftor in thelumacaftor/ivacaftor drug may be, for example, 50 mg, 100 mg, 150 mg,200 mg, 250 mg, 300 mg, 350 mg, 376 mg 400 mg or 450 mg, including allintegers and ranges therebetween. In some embodiments, when the totalreference dose of ivacaftor is 376 mg, the reduced total daily dose ofivacaftor in the lumacaftor/ivacaftor drug may be, for example, 50 mg,100 mg, 150 mg, 200 mg, 250 mg, 300 mg or 350 mg, including all integersand ranges therebetween. In some embodiments, when the total daily doseof ivacaftor is 250 mg, the reduced total daily dose of ivacaftor in thelumacaftor/ivacaftor drug may be, for example, 50 mg, 100 mg, 150 mg or200 mg, including all integers and ranges therebetween. Correspondingly,in some embodiments, when the individual reference dose of ivacaftor is188 mg, then the reduced individual reference dose of ivacaftor in thelumacaftor/ivacaftor drug may be, for example, 10 mg, 25 mg, 50 mg, 75mg, 100 mg, 125 mg or 150 mg, including all integers and rangestherebetween. In some embodiments, when the individual reference dose ofivacaftor is 125 mg then the reduced individual reference dose ofivacaftor in the lumacaftor/ivacaftor drug may be, for example, 10 mg,25 mg, 50 mg, 75 mg or 100 mg, including all integers and rangestherebetween.

In some embodiments, the CYP3A4 substrate drug is tezacaftor andivacaftor. The disease or condition treated with tezacaftor andivacaftor can include any disease or condition described herein or forwhich tezacaftor and ivacaftor is indicated. For example, in someembodiments, tezacaftor and ivacaftor is indicated for the treatment ofpatients with cystic fibrosis (CF) aged 12 years and older who arehomozygous for the F508del mutation or who have at least one mutation inthe cystic fibrosis transmembrane conductance regulator (CFTR) gene thatis responsive to tezacaftor/ivacaftor based on in vitro data and/orclinical evidence. Tezacaftor and ivacaftor may be administered as fixeddose combination tablets containing 100 mg tezacaftor and 150 mgivacaftor; and tablets containing 150 mg ivacaftor. In some embodiments,a tezacaftor/ivacaftor combination tablet and an ivacaftor tablet areadministered about 12 hours apart in adults and pediatric patients ages12 years and older. That is, when tezacaftor and ivacaftor is indicatedfor the treatment of patients with cystic fibrosis (CF) aged 12 yearsand older who are homozygous for the F508del mutation or who have atleast one mutation in the cystic fibrosis transmembrane conductanceregulator (CFTR) gene that is responsive to tezacaftor/ivacaftor basedon in vitro data and/or clinical evidence, the reference dose fortezacaftor is 100 mg administered once daily and the reference dose forivacaftor is 150 mg administered twice daily (total daily reference doseof tezacaftor is 100 mg and total daily reference dose of ivacaftor is300 mg). In various embodiments, the total daily reference dose oftezacaftor may be, for example, 10 mg, 25 mg, 50 mg, 75 mg, 100 mg, or200 mg; and the total daily reference dose of ivacaftor may be, forexample, 10 mg, 25 mg, 50 mg, 75 mg, 100 mg, 150 mg, 200 mg, 250 mg or300 mg. In accordance with certain embodiments of the presentdisclosure, when the total daily reference dose of tezacaftor andivacaftor is, for example, 100 mg tezacaftor/300 mg ivacaftor, thepatient will take a reduced total daily dose of tezacaftor and ivacaftor(either concomitantly with posaconazole or after a delay period afterstopping posaconazole). In some embodiments, the reduced total dailydose of tezacaftor may be, for example, 10 mg, 25 mg, 50 mg, or 75 mg,including all integers and ranges therebetween and the reduced totaldaily dose of ivacaftor may be, for example, 50 mg, 75 mg, 100 mg, 150mg, 200 mg or 250 mg, including all integers and ranges therebetween.When the total daily reference dose of tezacaftor 75 mg, the reducedtotal daily dose of tezacaftor may be, for example, 10 mg, 25 mg or 50mg, including all integers and ranges therebetween. When the total dailyreference dose of ivacaftor is 200 mg, the reduced total daily dose ofivacaftor may be, for example, 50 mg, 75 mg, 100 mg, or 150 mg,including all integers and ranges therebetween. Correspondingly, whenthe individual reference dose of tezacaftor 100 mg, the reducedindividual reference dose of tezacaftor may be, for example, 10 mg, 25mg, 50 mg or 75 mg, including all integers and ranges therebetween. Whenthe individual reference dose of ivacaftor is 150 mg, the reducedindividual reference dose of ivacaftor may be, for example, 10 mg, 25mg, 50 mg, 75 mg, or 100 mg, including all integers and rangestherebetween.

In some embodiments, the CYP3A4 substrate drug is ivosidenib. Thedisease or condition treated with ivosidenib can include any disease orcondition described herein or for which ivosidenib is indicated. Forexample, in some embodiments, ivosidenib is indicated for the treatmentof adult patients with relapsed or refractory acute myeloid leukemia(AML) with a susceptible IDH1 mutation as detected by an FDA-approvedtest. Ivosidenib may be administered in a 250 mg dosage form. In someembodiments, 500 mg of ivosidenib is administered once daily. Forexample, when ivosidenib is indicated for the treatment of adultpatients with relapsed or refractory acute myeloid leukemia (AML) with asusceptible IDH1 mutation as detected by an FDA-approved test, thereference dose is 500 mg administered once daily (total daily referencedose is 500 mg). In various embodiments, the total daily reference doseof ivosidenib may be, for example, 125 mg, 250 mg, 375 mg, or 500 mg. Inaccordance with certain embodiments of the present disclosure, when thetotal daily reference dose of ivosidenib is, for example, 500 mg, thepatient will take a reduced total daily dose of ivosidenib (eitherconcomitantly with posaconazole or after a delay period after stoppingposaconazole). In some embodiments, the reduced total daily dose ofivosidenib may be, for example, 10 mg, 25 mg, 50 mg, 100 mg, 125 mg, 150mg, 200 mg, 250 mg, 300 mg, 375 mg, 400 mg, 450 mg, or 470 mg, includingall integers and ranges therebetween. When the total daily referencedose of ivosidenib is 500 mg, the reduced total daily dose of ivosidenibmay be, for example, 10 mg, 25 mg, 50 mg, 100 mg, 125 mg, 150 mg, 200mg, 250 mg, 300 mg, 375 mg, 400 mg, 450 mg, or 470 mg, including allintegers and ranges therebetween. When the total daily reference dose ofivosidenib is 250 mg, the reduced total daily dose of ivosidenib may be,for example, 10 mg, 25 mg, 50 mg, 100 mg, 125 mg, 150 mg, or 200 mg,including all integers and ranges therebetween. Correspondingly, whenthe individual reference dose of ivosidenib is 250 mg, the reducedindividual reference dose of ivosidenib may be, for example, 10 mg, 25mg, 50 mg, 100 mg, 125 mg, 150 mg, or 200 mg, including all integers andranges therebetween.

In some embodiments, the CYP3A4 substrate drug is naloxegol. The diseaseor condition treated with naloxegol can include any disease or conditiondescribed herein or for which naloxegol is indicated. For example, insome embodiments, naloxegol is indicated for the treatment ofopioid-induced constipation (OIC) in adult patients with chronicnon-cancer pain, including patients with chronic pain related to priorcancer or its treatment who do not require frequent (e.g., weekly)opioid dosage escalation. Naloxegol may be administered in a 12.5 mg or25 mg dosage form. In some embodiments, naloxegol is administered oncedaily up to a total daily dose of 25 mg. For example, when naloxegol isindicated for the treatment of opioid-induced constipation (OIC) inadult patients with chronic non-cancer pain, including patients withchronic pain related to prior cancer or its treatment who do not requirefrequent (e.g., weekly) opioid dosage escalation, the reference dose is25 mg, administered once daily (total daily reference dose is 25 mg). Ifthe reference dose of 25 mg is not tolerated, reduce to 12.5 mg oncedaily (total daily reference dose is 12.5 mg). For renal impairment(CLcr <60 mL/min), the reference dose is 12.5 mg once daily andincreases to 25 mg once daily if tolerated and monitor for adversereactions. Thus, in various embodiments, the total daily reference doseof naloxegol may be, for example, 5 mg, 10 mg, 15 mg, 20 mg, or 25 mg.In accordance with certain embodiments of the present disclosure, whenthe total daily reference dose of naloxegol is, for example, 25 mg, thepatient will take a reduced total daily dose of naloxegol (eitherconcomitantly with posaconazole or after a delay period after stoppingposaconazole). In some embodiments, the reduced total daily dose ofnaloxegol is, for example, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg,19 mg, 20 mg, 21 mg, 22 mg, 23 mg, or 24 mg, including all integers andranges therebetween. When the total daily reference dose of naloxegol is25 mg, the reduced total daily dose of naloxegol is, for example, 1 mg,2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23mg, or 24 mg, including all integers and ranges therebetween. When thetotal daily reference dose of naloxegol is 12.5 mg, the reduced totaldaily dose of naloxegol is, for example, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, or 12 mg, including all integers andranges therebetween. Correspondingly, when the individual reference doseof naloxegol is 25 mg, the reduced individual reference dose ofnaloxegol is, for example, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg,19 mg, 20 mg, 21 mg, 22 mg, 23 mg, or 24 mg, including all integers andranges therebetween. When the individual reference dose of naloxegol is12.5 mg, the reduced individual reference dose of naloxegol is, forexample, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11mg, or 12 mg, including all integers and ranges therebetween.

In some embodiments, the CYP3A4 substrate drug is nilotinib. The diseaseor condition treated with nilotinib can include any disease or conditiondescribed herein or for which nilotinib is indicated. For example, insome embodiments, nilotinib is indicated for the treatment of adult andpediatric patients greater than or equal to 1 year of age with newlydiagnosed Philadelphia chromosome positive chronic myeloid leukemia (Ph+CML) in chronic phase. In some embodiments, nilotinib is indicated forthe treatment of adult patients with chronic phase (CP) and acceleratedphase (AP) Ph+ CML resistant to or intolerant to prior therapy thatincluded imatinib. In some embodiments, nilotinib is indicated for thetreatment of pediatric patients greater than or equal to 1 year of agewith Ph+ CML-CP resistant or intolerant to prior tyrosine-kinaseinhibitor (TKI) therapy. Nilotinib may be administered in a 50 mg, 150mg or 200 mg dosage form. In some embodiments, nilotinib is administeredonce daily up to a total daily dose of 400 mg. In some embodiments,nilotinib is administered twice daily up to a total daily dose of 800mg. For example, when nilotinib is indicated for the treatment of adultsnewly diagnosed with Ph+ CML-CP, the reference dose is 300 mg,administered twice daily (total daily reference dose is 600 mg). Forexample, when nilotinib is indicated for the treatment of adults withresistant or intolerant to Ph+ CML-CP, the reference dose is 400 mg,administered twice daily (total daily reference dose is 800 mg). Forexample, when nilotinib is indicated for the treatment of pediatricsnewly diagnosed with Ph+ CML-CP, the reference dose is 230 mg/m²,administered twice daily, rounded to the nearest 50 mg dose (total dailyreference dose is 400 mg). For example, when nilotinib is indicated forthe treatment of adults with resistant or intolerant to Ph+ CML-CP, thereference dose is 400 mg, administered twice daily (total dailyreference dose is 800 mg). Thus, in various embodiments, the total dailyreference dose of nilotinib may be, for example, 50 mg, 100 mg, 150 mg,200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg,650 mg, 700 mg, 750 mg, or 800 mg, including all integers and rangestherebetween. In accordance with certain embodiments of the presentdisclosure, when the total daily reference dose of nilotinib is, forexample, 800 mg, the patient will take a reduced total daily dose ofnilotinib (either concomitantly with posaconazole or after a delayperiod after stopping posaconazole). In some embodiments, the reducedtotal daily dose of nilotinib is, for example, 50 mg, 100 mg, 150 mg,200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg,650 mg, 700 mg, or 750 mg, including all integers and rangestherebetween. When the total daily reference dose of nilotinib is 800mg, the reduced total daily dose of nilotinib is, for example, 50 mg,100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg,550 mg, 600 mg, 650 mg, 700 mg, or 750 mg, including all integers andranges therebetween. When the total daily reference dose of nilotinib is400 mg, the reduced total daily dose of nilotinib is, for example, 50mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, or 350 mg, including allintegers and ranges therebetween. Correspondingly, when the individualreference dose of nilotinib is 200 mg, the reduced individual referencedose of nilotinib is, for example, 50 mg, 100 mg, or 150 mg, includingall integers and ranges therebetween. When the individual reference doseof nilotinib is 150 mg, the reduced individual reference dose ofnilotinib is, for example, 50 mg or 100 mg, including all integers andranges therebetween.

In some embodiments, the CYP3A4 substrate drug is olaparib (Capsules).The disease or condition treated with olaparib can include any diseaseor condition described herein or for which olaparib is indicated. Forexample, in some embodiments, olaparib is indicated for the treatment ofadult patients with deleterious or suspected deleterious germlineBRCA-mutated advanced ovarian cancer who have been treated with three ormore prior lines of chemotherapy. Olaparib may be administered in a 50mg dosage form. In some embodiments, olaparib is administered twicedaily up to a total daily dose of 800 mg with or without food. Forexample, when olaparib is indicated for the treatment of adult patientswith deleterious or suspected deleterious germline BRCA-mutated advancedovarian cancer who have been treated with three or more prior lines ofchemotherapy, the reference dose is 400 mg, administered twice daily(total daily reference dose is 800 mg) with or without food. Formoderate renal impairment (CLcr 31-50 mL/min), the reference dosereduces to 300 mg twice daily (total daily reference dose is 600 mg).Thus, in various embodiments, the total daily reference dose of olaparibmay be, for example, 25 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750mg, or 800 mg, including all integers and ranges therebetween. Inaccordance with certain embodiments of the present disclosure, when thetotal daily reference dose of olaparib is, for example, 800 mg, thepatient will take a reduced total daily dose of olaparib (eitherconcomitantly with posaconazole or after a delay period after stoppingposaconazole). In some embodiments, the reduced total daily dose ofolaparib is, for example, 25 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg,300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg,or 750 mg, including all integers and ranges therebetween. When thetotal daily reference dose of olaparib is 800 mg, the reduced totaldaily dose of olaparib is, for example, 25 mg, 50 mg, 100 mg, 150 mg,200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg,650 mg, 700 mg, or 750 mg, including all integers and rangestherebetween. When the total daily reference dose of olaparib is 600 mg,the reduced total daily dose of olaparib is, for example, 25 mg, 50 mg,100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg,or 550 mg, including all integers and ranges therebetween.Correspondingly, when the individual reference dose of olaparib is 400mg, the reduced individual reference dose of olaparib is, for example,25 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, or 350 mg,including all integers and ranges therebetween. When the individualreference dose of olaparib is 300 mg, the reduced individual referencedose of olaparib is, for example, 25 mg, 50 mg, 100 mg, 150 mg, 200 mg,or 250 mg, including all integers and ranges therebetween. When theindividual reference dose of olaparib is 50 mg, the reduced individualreference dose of olaparib is, for example, 25 mg.

In some embodiments, the CYP3A4 substrate drug is olaparib (Tablets).The disease or condition treated with olaparib can include any diseaseor condition described herein or for which olaparib is indicated. Forexample, in some embodiments, olaparib is indicated for the maintenancetreatment of adult patients with recurrent epithelial ovarian, fallopiantube or primary peritoneal cancer, who are in a complete or partialresponse to platinum-based chemotherapy. In some embodiments, olaparibis indicated for the treatment of adult patients with deleterious orsuspected deleterious germline BRCA-mutated (gBRCAm) advanced ovariancancer who have been treated with three or more prior lines ofchemotherapy. In some embodiments, olaparib is indicated in patientswith deleterious or suspected deleterious gBRCAm, human epidermal growthfactor receptor 2 (HER2)-negative metastatic breast cancer who have beentreated with chemotherapy in the neoadjuvant, adjuvant or metastaticsetting. Olaparib may be administered in a 150 mg or 100 mg dosage form.In some embodiments, olaparib is twice daily up to a total daily dose of600 mg with or without food. For example, when olaparib is indicated forthe maintenance treatment of adult patients with recurrent epithelialovarian, fallopian tube or primary peritoneal cancer, who are in acomplete or partial response to platinum-based chemotherapy, thereference dose is 300 mg, administered twice daily (total dailyreference dose is 600 mg). For example, when olaparib is indicated forthe treatment of adult patients with deleterious or suspecteddeleterious germline BRCA-mutated (gBRCAm) advanced ovarian cancer whohave been treated with three or more prior lines of chemotherapy, thereference dose is 300 mg, administered twice daily (total dailyreference dose is 600 mg). For example, when olaparib is indicated forin patients with deleterious or suspected deleterious gBRCAm, humanepidermal growth factor receptor 2 (HER2)-negative metastatic breastcancer who have been treated with chemotherapy in the neoadjuvant,adjuvant or metastatic setting, the reference dose is 300 mg,administered twice daily (total daily reference dose is 600 mg). Formoderate renal impairment (CLcr 31-50 mL/min), the reference dosereduces to 200 mg twice daily (total daily reference dose is 400 mg).Thus, in various embodiments, the total daily reference dose of olaparibmay be, for example, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350mg, 400 mg, 450 mg, 500 mg, 550 mg, or 600 mg, including all integersand ranges therebetween. In accordance with certain embodiments of thepresent disclosure, when the total daily reference dose of olaparib is,for example, 600 mg, the patient will take a reduced total daily dose ofolaparib (either concomitantly with posaconazole or after a delay periodafter stopping posaconazole). In some embodiments, the reduced totaldaily dose of olaparib is, for example, 50 mg, 100 mg, 150 mg, 200 mg,250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, or 550 mg, including allintegers and ranges therebetween. When the total daily reference dose ofolaparib is 600 mg, the reduced total daily dose of olaparib is, forexample, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg,450 mg, 500 mg, or 550 mg, including all integers and rangestherebetween. When the total daily reference dose of olaparib is 400 mg,the reduced total daily dose of olaparib is, for example, 50 mg, 100 mg,150 mg, 200 mg, 250 mg, 300 mg, or 350 mg, including all integers andranges therebetween. When the total daily reference dose of olaparib is200 mg, the reduced total daily dose of olaparib is, for example, 50 mg,100 mg, or 150 mg, including all integers and ranges therebetween.Correspondingly, when the individual reference dose of olaparib is 150mg, the reduced individual reference dose of olaparib is, for example,50 mg or 100 mg, including all integers and ranges therebetween. Whenthe individual reference dose of olaparib is 100 mg, the reducedindividual reference dose of olaparib is, for example, 50 mg.

In some embodiments, the CYP3A4 substrate drug is palbociclib. Thedisease or condition treated with palbociclib can include any disease orcondition described herein or for which palbociclib is indicated. Forexample, in some embodiments, palbociclib is indicated for the treatmentof hormone receptor (HR)-positive, human epidermal growth factorreceptor 2 (HER2)-negative advanced or metastatic breast cancer incombination with an aromatase inhibitor as initial endocrine basedtherapy in postmenopausal women. For example, in some embodiments,palbociclib is indicated for the treatment of hormone receptor(HR)-positive, human epidermal growth factor receptor 2 (HER2)-negativeadvanced or metastatic breast cancer in combination with fulvestrant inwomen with disease progression following endocrine therapy. Palbociclibmay be administered in a 125 mg, 100 mg or 75 mg dosage form. In someembodiments, palbociclib is administered once daily up to a total dailydose of 125 mg with food for 21 days followed by 7 days off treatment.For example, when palbociclib is indicated for the treatment of hormonereceptor (HR)-positive, human epidermal growth factor receptor 2(HER2)-negative advanced or metastatic breast cancer in combination withan aromatase inhibitor as initial endocrine based therapy inpostmenopausal women, the reference dose is 125 mg, administered oncedaily (total daily reference dose is 125 mg). For example, whenpalbociclib is indicated for the treatment of hormone receptor(HR)-positive, human epidermal growth factor receptor 2 (HER2)-negativeadvanced or metastatic breast cancer in combination with fulvestrant inwomen with disease progression following endocrine therapy, thereference dose is 125 mg, administered once daily (total daily referencedose is 125 mg). Thus, in various embodiments, the total daily referencedose of palbociclib may be, for example, 25 mg, 50 mg, 75 mg, 100 mg or125 mg, including all integers and ranges therebetween. In accordancewith certain embodiments of the present disclosure, when the total dailyreference dose of palbociclib is, for example, 125 mg, the patient willtake a reduced total daily dose of palbociclib (either concomitantlywith posaconazole or after a delay period after stopping posaconazole).In some embodiments, the reduced total daily dose of palbociclib is, forexample, 25 mg, 50 mg, 75 mg, or 100 mg, including all integers andranges therebetween. When the total daily reference dose of palbociclibis 125 mg, the reduced total daily dose of palbociclib is, for example,25 mg, 50 mg, 75 mg, or 100 mg, including all integers and rangestherebetween. When the total daily reference dose of palbociclib is 125mg, the reduced total daily dose of palbociclib is, for example, 25 mg,50 mg, 75 mg, or 100 mg, including all integers and ranges therebetween.Correspondingly, when the individual reference dose of palbociclib is125 mg, the reduced individual reference dose of palbociclib is, forexample, 25 mg, 50 mg, 75 mg, or 100 mg, including all integers andranges therebetween. When the individual reference dose of palbociclibis 100 mg, the reduced individual reference dose of palbociclib is, forexample, 25 mg, 50 mg, or 75 mg, including all integers and rangestherebetween. When the individual reference dose of palbociclib is 75mg, the reduced individual reference dose of palbociclib is, forexample, 25 mg, or 50 mg, including all integers and rangestherebetween.

In some embodiments, the CYP3A4 substrate drug is panobinostat. Thedisease or condition treated with panobinostat can include any diseaseor condition described herein or for which panobinostat is indicated.For example, in some embodiments, panobinostat is indicated for thetreatment of patients with multiple myeloma who have received at least 2prior regimens, including bortezomib and an immunomodulatory agent.Panobinostat may be administered in a 10 mg, 15 mg, or 20 mg dosageform. In some embodiments, panobinostat is administered once every otherday for 3 doses per week (on Days 1, 3, 5, 8, 10, and 12) of Weeks 1 and2 of each 21-day cycle for 8 cycles, up to a total every other day doseof 20 mg. For example, when panobinostat is indicated for the treatmentof patients with multiple myeloma who have received at least 2 priorregimens, including bortezomib and an immunomodulatory agent, thereference dose is 20 mg, administered once every other day for threetimes weekly (total every other day reference dose is 20 mg). Thus, invarious embodiments, the total every other day reference dose ofpanobinostat may be, for example, 10 mg, 15 mg, or 20 mg, including allintegers and ranges therebetween. In accordance with certain embodimentsof the present disclosure, when the total every other day reference doseof panobinostat is, for example, 20 mg, the patient will take a reducedtotal every other day dose of panobinostat (either concomitantly withposaconazole or after a delay period after stopping posaconazole). Insome embodiments, the reduced total every other day dose of panobinostatis, for example, 5 mg, 7.5 mg, 10 mg, or 15 mg, including all integersand ranges therebetween. When the total every other day reference doseof panobinostat is 20 mg, the reduced total every other day dose ofpanobinostat is, for example, 5 mg, 7.5 mg, 10 mg, or 15 mg, includingall integers and ranges therebetween. Correspondingly, when theindividual reference dose of panobinostat is 20 mg, the reducedindividual reference dose of panobinostat is, for example, 5 mg, 7.5 mg,10 mg, or 15 mg, including all integers and ranges therebetween. Whenthe individual reference dose of panobinostat is 15 mg, the reducedindividual reference dose of panobinostat is, for example, 5 mg, 7.5 mg,or 10 mg, including all integers and ranges therebetween. When theindividual reference dose of panobinostat is 10 mg, the reducedindividual reference dose of panobinostat is, for example, 5 mg, or 7.5mg, including all integers and ranges therebetween.

In some embodiments, the CYP3A4 substrate drug is pazopanib. The diseaseor condition treated with pazopanib can include any disease or conditiondescribed herein or for which pazopanib is indicated. For example, insome embodiments, pazopanib is indicated for the treatment of patientswith advanced renal cell carcinoma. For example, in some embodiments,pazopanib is indicated for the treatment of patients with advanced softtissue sarcoma who have received prior chemotherapy. Pazopanib may beadministered in a 200 mg dosage form. In some embodiments, pazopanib isadministered once daily up to a total daily dose of 800 mg without food(at least 1 hour before or 2 hours after a meal). For baseline moderatehepatic impairment, pazopanib is administered once daily up to 200 mg.For example, when pazopanib is indicated for the treatment of patientswith advanced renal cell carcinoma, the reference dose is 800 mg,administered once daily (total daily reference dose is 800 mg). Forexample, when pazopanib is indicated for the treatment of patients withadvanced soft tissue sarcoma who have received prior chemotherapy, thereference dose is 800 mg, administered once daily (total daily referencedose is 800 mg). Thus, in various embodiments, the total daily referencedose of pazopanib may be, for example, 50 mg, 100 mg, 150 mg, 200 mg,250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg,700 mg, 750 mg, or 800 mg. In accordance with certain embodiments of thepresent disclosure, when the total daily reference dose of pazopanib is,for example, 800 mg, the patient will take a reduced total daily dose ofpazopanib (either concomitantly with posaconazole or after a delayperiod after stopping posaconazole). In some embodiments, the reducedtotal daily dose of pazopanib is, for example, 50 mg, 100 mg, 150 mg,200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg,650 mg, 700 mg, or 750 mg, including all integers and rangestherebetween. When the total daily reference dose of pazopanib is 800mg, the reduced total daily dose of pazopanib is, for example, 50 mg,100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg,550 mg, 600 mg, 650 mg, 700 mg, or 750 mg, including all integers andranges therebetween. When the total daily reference dose of pazopanib is600 mg, the reduced total daily dose of pazopanib is, for example, 50mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500mg, or 550 mg, including all integers and ranges therebetween. When thetotal daily reference dose of pazopanib is 400 mg, the reduced totaldaily dose of pazopanib is, for example, 50 mg, 100 mg, 150 mg, 200 mg,250 mg, 300 mg, or 350 mg, including all integers and rangestherebetween. When the total daily reference dose of pazopanib is 200mg, the reduced total daily dose of pazopanib is, for example, 50 mg,100 mg, or 150 mg, including all integers and ranges therebetween.Correspondingly, when the individual reference dose of pazopanib is 200mg, the reduced individual reference dose of pazopanib is, for example,50 mg, 100 mg, or 150 mg, including all integers and rangestherebetween.

In some embodiments, the CYP3A4 substrate drug is regorafenib. Thedisease or condition treated with regorafenib can include any disease orcondition described herein or for which regorafenib is indicated. Forexample, in some embodiments, regorafenib is indicated for the treatmentof patients with metastatic colorectal cancer (CRC) who have beenpreviously treated with fluoropyrimidine-, oxaliplatin- andirinotecan-based chemotherapy, an anti-VEGF therapy, and, if RASwild-type, an anti-EGFR therapy. In some embodiments, regorafenib isindicated for the treatment of patients with locally advanced,unresectable or metastatic gastrointestinal stromal tumor (GIST) whohave been previously treated with imatinib mesylate and sunitinibmalate. In some embodiments, regorafenib is indicated for the treatmentof patients with hepatocellular carcinoma (HCC) who have been previouslytreated with sorafenib. Regorafenib may be administered in a 40 mgdosage form. In some embodiments, regorafenib is administered once dailyup to a total daily dose of 160 mg for the first 21 days of each 28-daycycle. For example, when regorafenib is indicated for the treatment ofpatients with metastatic colorectal cancer (CRC) who have beenpreviously treated with fluoropyrimidine-, oxaliplatin- andirinotecan-based chemotherapy, an anti-VEGF therapy, and, if RASwild-type, an anti-EGFR therapy, the reference dose is 160 mg,administered once daily (total daily reference dose is 160 mg). Forexample, when regorafenib is indicated for the treatment of patientswith locally advanced, unresectable or metastatic gastrointestinalstromal tumor (GIST) who have been previously treated with imatinibmesylate and sunitinib malate, the reference dose is 160 mg,administered once daily (total daily reference dose is 160 mg). Forexample, when regorafenib is indicated for the treatment of patientswith hepatocellular carcinoma (HCC) who have been previously treatedwith sorafenib, the reference dose is 160 mg, administered once daily(total daily reference dose is 160 mg). Thus, in various embodiments,the total daily reference dose of regorafenib may be, for example, 20mg, 40 mg, 60 mg, 80 mg, 100 mg, 120 mg, 140 mg, or 160 mg, includingall integers and ranges therebetween. In accordance with certainembodiments of the present disclosure, when the total daily referencedose of regorafenib is, for example, 160 mg, the patient will take areduced total daily dose of regorafenib (either concomitantly withposaconazole or after a delay period after stopping posaconazole). Insome embodiments, the reduced total daily dose of regorafenib is 20 mg,40 mg, 60 mg, 80 mg, 100 mg, 120 mg, or 140 mg. When the total dailyreference dose of regorafenib is 160 mg, the reduced total daily dose ofregorafenib is, for example, 20 mg, 40 mg, 60 mg, 80 mg, 100 mg, 120 mg,or 140 mg, including all integers and ranges therebetween. When thetotal daily reference dose of regorafenib is 120 mg, the reduced totaldaily dose of regorafenib is, for example, 20 mg, 40 mg, 60 mg, 80 mg,or 100 mg, including all integers and ranges therebetween. When thetotal daily reference dose of regorafenib is 80 mg, the reduced totaldaily dose of regorafenib is, for example, 20 mg, 40 mg, or 60 mg,including all integers and ranges therebetween. Correspondingly, whenthe individual reference dose of regorafenib is 40 mg, the reducedindividual reference dose of regorafenib is, for example, 20 mg.

In some embodiments, the CYP3A4 substrate drug is rivaroxaban. Thedisease or condition treated with rivaroxaban can include any disease orcondition described herein or for which rivaroxaban is indicated. Forexample, in some embodiments, rivaroxaban is indicated to reduce therisk of stroke and systemic embolism in patients with nonvalvular atrialfibrillation. In some embodiments, rivaroxaban is indicated for thetreatment of deep vein thrombosis (DVT). In some embodiments,rivaroxaban is indicated for the treatment of pulmonary embolism (PE).In some embodiments, rivaroxaban is indicated for the reduction in therisk of recurrence of DVT and/or PE in patients at continued risk forrecurrent DVT and/or PE after completion of initial treatment lasting atleast 6 months. In some embodiments, rivaroxaban is indicated for theprophylaxis of DVT, which may lead to PE in patients undergoing knee orhip replacement surgery. In some embodiments, rivaroxaban is indicatedin combination with aspirin, to reduce the risk of major cardiovascularevents (cardiovascular (CV) death, myocardial infarction (MI) andstroke) in patients with chronic coronary artery disease (CAD) orperipheral artery disease (PAD). Rivaroxaban may be administered in a2.5 mg, 10 mg, 15 mg, or 20 mg dosage form. In some embodiments,rivaroxaban is administered twice daily up to a total daily dose of 40mg. In some embodiments, rivaroxaban is administered twice daily up to atotal daily dose of 30 mg. In some embodiments, rivaroxaban isadministered once daily up to a total daily dose of 20 mg. In someembodiments, rivaroxaban is administered once daily up to a total dailydose of 15 mg. In some embodiments, rivaroxaban is administered oncedaily up to a total daily dose of 10 mg. In some embodiments,rivaroxaban is administered once daily up to a total daily dose of 2.5mg. For example, when rivaroxaban is indicated to reduce the risk ofstroke and systemic embolism in patients with nonvalvular atrialfibrillation, the reference dose is 20 mg, administered once daily(total daily reference dose is 20 mg) with the evening meal for patientswith CrCl >50 mL/min, while the reference dose is 15 mg, administeredonce daily (total daily reference dose is 15 mg) with the evening mealfor patients with CrCl≤50 mL/min. For example, when rivaroxaban isindicated for the treatment of deep vein thrombosis (DVT), the referencedose is 15 mg administered twice daily (total daily reference dose is 30mg) with food for the first 21 days and followed by 20 mg administeredonce daily (total daily reference dose is 20 mg) with food for theremaining treatment. For example, when rivaroxaban is indicated for thetreatment of pulmonary embolism (PE), the reference dose is 15 mgadministered twice daily (total daily reference dose is 30 mg) with foodfor the first 21 days and followed by 20 mg administered once daily(total daily reference dose is 20 mg) with food for the remainingtreatment. For example, when rivaroxaban is indicated for the reductionin the risk of recurrence of DVT and/or PE in patients at continued riskfor recurrent DVT and/or PE after completion of initial treatmentlasting at least 6 months, the reference dose is 10 mg, administeredonce daily (total daily reference dose is 10 mg) with or without food.For example, when rivaroxaban is indicated for the prophylaxis of DVT,which may lead to PE in patients undergoing knee or hip replacementsurgery, the reference dose is 10 mg, administered once daily (totaldaily reference dose is 10 mg) with or without food. For example, whenrivaroxaban is indicated in combination with aspirin, to reduce the riskof major cardiovascular events (cardiovascular (CV) death, myocardialinfarction (MI) and stroke) in patients with chronic coronary arterydisease (CAD) or peripheral artery disease (PAD), the reference dose is2.5 mg, administered twice daily (total daily reference dose is 5 mg)with or without food, in combination with aspirin (75-100 mg) oncedaily. Thus, in various embodiments, the total daily reference dose ofrivaroxaban may be, for example, 1 mg, 1.25 mg, 1.5 mg, 2 mg, 2.5 mg, 3mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg, 31 mg, 32 mg, 33 mg, 34mg, 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, or 40 mg, including all integersand ranges therebetween. In accordance with certain embodiments of thepresent disclosure, when the total daily reference dose of rivaroxabanis, for example, 40 mg, the patient will take a reduced total daily doseof rivaroxaban (either concomitantly with posaconazole or after a delayperiod after stopping posaconazole). In some embodiments, the reducedtotal daily dose of rivaroxaban is, for example, 1 mg, 1.25 mg, 1.5 mg,2 mg, 2.5 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg, 31 mg, 32mg, 33 mg, 34 mg, 35 mg, 36 mg, 37 mg, 38 mg, or 39 mg, including allintegers and ranges therebetween. When the total daily reference dose ofrivaroxaban is 40 mg, the reduced total daily dose of rivaroxaban is,for example, 1 mg, 1.25 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 4 mg, 5 mg, 6mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg,17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27mg, 28 mg, 29 mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg, 35 mg, 36 mg, 37mg, 38 mg, or 39 mg, including all integers and ranges therebetween. Inaccordance with certain embodiments of the present disclosure, when thetotal daily reference dose of rivaroxaban is, for example, 30 mg, thepatient will take a reduced total daily dose of rivaroxaban (eitherconcomitantly with posaconazole or after a delay period after stoppingposaconazole). In some embodiments, the reduced total daily dose ofrivaroxaban is, for example, 1 mg, 1.25 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg,4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg,15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25mg, 26 mg, 27 mg, 28 mg, or 29 mg, including all integers and rangestherebetween. When the total daily reference dose of rivaroxaban is 30mg, the reduced total daily dose of rivaroxaban is, for example, 1 mg,1.25 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg,10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, or 29 mg,including all integers and ranges therebetween. When the total dailyreference dose of rivaroxaban is 20 mg, the reduced total daily dose ofrivaroxaban is, for example, 1 mg, 1.25 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg,4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg,15 mg, 16 mg, 17 mg, 18 mg, or 19 mg, including all integers and rangestherebetween. When the total daily reference dose of rivaroxaban is 15mg, the reduced total daily dose of rivaroxaban is 1 mg, 1.25 mg, 1.5mg, 2 mg, 2.5 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11mg, 12 mg, 13 mg, or 14 mg, including all integers and rangestherebetween. When the total daily reference dose of rivaroxaban is 10mg, the reduced total daily dose of rivaroxaban is, for example, 1 mg,1.25 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, or 9mg, including all integers and ranges therebetween. When the total dailyreference dose of rivaroxaban is 5 mg, the reduced total daily dose ofrivaroxaban is 1 mg, 1.25 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, or 4 mg,including all integers and ranges therebetween. Correspondingly, whenthe individual reference dose of rivaroxaban is 20 mg, the reducedindividual reference dose of rivaroxaban is the reduced total daily doseof rivaroxaban is, for example, 1 mg, 1.25 mg, 1.5 mg, 2 mg, 2.5 mg, 3mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14mg, 15 mg, 16 mg, 17 mg, 18 mg, or 19 mg, including all integers andranges therebetween. When the individual reference dose of rivaroxabanis 15 mg, the reduced individual reference dose of rivaroxaban is thereduced total daily dose of rivaroxaban is, for example, 1 mg, 1.25 mg,1.5 mg, 2 mg, 2.5 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg,11 mg, 12 mg, 13 mg, or 14 mg, including all integers and rangestherebetween. When the individual reference dose of rivaroxaban is 10mg, the reduced individual reference dose of rivaroxaban is the reducedtotal daily dose of rivaroxaban is, for example, 1 mg, 1.25 mg, 1.5 mg,2 mg, 2.5 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, or 9 mg, including allintegers and ranges therebetween. When the individual reference dose ofrivaroxaban is 2.5 mg, the reduced individual reference dose ofrivaroxaban is the reduced total daily dose of rivaroxaban is, forexample, 1 mg, 1.25 mg, 1.5 mg, or 2 mg, including all integers andranges therebetween.

In some embodiments, the CYP3A4 substrate drug is ruxolitinib. Thedisease or condition treated with ruxolitinib can include any disease orcondition described herein or for which ruxolitinib is indicated. Forexample, in some embodiments, ruxolitinib is indicated for treatment ofpatients with intermediate or high-risk myelofibrosis, including primarymyelofibrosis, post-polycythemia vera myelofibrosis and post-essentialthrombocythemia myelofibrosis. In some embodiments, ruxolitinib isindicated for treatment of patients with polycythemia vera who have hadan inadequate response to or are intolerant of hydroxyurea. Ruxolitinibmay be administered in a 5 mg, 10 mg, 15 mg, 20 mg or 25 mg dosage form.In some embodiments, ruxolitinib is administered twice daily up to atotal daily dose of 50 mg. For example, when ruxolitinib is indicatedfor treatment of patients with intermediate or high-risk myelofibrosis,including primary myelofibrosis, post-polycythemia vera myelofibrosisand post-essential thrombocythemia myelofibrosis, the reference dose is20 mg, administered twice daily (total daily reference dose is 40 mg)when patient's baseline platelet count is greater than 200×10⁹/L. Forexample, when ruxolitinib is indicated for treatment of patients withintermediate or high-risk myelofibrosis, including primarymyelofibrosis, post-polycythemia vera myelofibrosis and post-essentialthrombocythemia myelofibrosis, the reference dose is 15 mg, administeredtwice daily (total daily reference dose is 30 mg) when patient'sbaseline platelet count is 100×10⁹/L to 200×10⁹/L. For example, whenruxolitinib is indicated for treatment of patients with intermediate orhigh-risk myelofibrosis, including primary myelofibrosis,post-polycythemia vera myelofibrosis and post-essential thrombocythemiamyelofibrosis, the reference dose is 5 mg, administered twice daily(total daily reference dose is 10 mg) when patient's baseline plateletcount is 50×10⁹/L to less than 100×10⁹/L. For example, when ruxolitinibis indicated for treatment of patients with polycythemia vera who havehad an inadequate response to or are intolerant of hydroxyurea, thereference dose is 10 mg, administered twice daily (total daily referencedose is 20 mg). Thus, in various embodiments, the total daily referencedose of ruxolitinib may be, for example, 2.5 mg, 5 mg, 7.5 mg, 10 mg,12.5 mg, 15 mg, 17.5 mg, 20 mg, 22.5 mg, 25 mg, 27.5 mg, 30 mg, 32.5 mg,35 mg, 37.5 mg, 40 mg, 42.5 mg, 45, 47.5 mg, or 50 mg. In accordancewith certain embodiments of the present disclosure, when the total dailyreference dose of ruxolitinib is, for example, 40 mg, the patient willtake a reduced total daily dose of ruxolitinib (either concomitantlywith posaconazole or after a delay period after stopping posaconazole).In some embodiments, the reduced total daily dose of ruxolitinib is, forexample, 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, 17.5 mg, 20 mg,22.5 mg, 25 mg, 27.5 mg, 30 mg, 32.5 mg, 35 mg, or 37.5 mg, 40 mg, 42.5mg, 45, or 47.5 mg, including all integers and ranges therebetween. Whenthe total daily reference dose of ruxolitinib is 50 mg, the reducedtotal daily dose of ruxolitinib is, for example, 2.5 mg, 5 mg, 7.5 mg,10 mg, 12.5 mg, 15 mg, 17.5 mg, 20 mg, 22.5 mg, 25 mg, 27.5 mg, 30 mg,32.5 mg, 35 mg, or 37.5 mg, 40 mg, 42.5 mg, 45, or 47.5 mg, includingall integers and ranges therebetween. When the total daily referencedose of ruxolitinib is 40 mg, the reduced total daily dose ofruxolitinib is, for example, 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15mg, 17.5 mg, 20 mg, 22.5 mg, 25 mg, 27.5 mg, 30 mg, 32.5 mg, 35 mg, or37.5 mg, including all integers and ranges therebetween. When the totaldaily reference dose of ruxolitinib is 30 mg, the reduced total dailydose of ruxolitinib is, for example, 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5mg, 15 mg, 17.5 mg, 20 mg, 22.5 mg, 25 mg, or 27.5 mg, including allintegers and ranges therebetween. When the total daily reference dose ofruxolitinib is 20 mg, the reduced total daily dose of ruxolitinib is,for example, 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, or 17.5 mg,including all integers and ranges therebetween. When the total dailyreference dose of ruxolitinib is 10 mg, the reduced total daily dose ofruxolitinib is, for example, 2.5 mg, 5 mg, or 7.5 mg, including allintegers and ranges therebetween. Correspondingly, when the individualreference dose of ruxolitinib is 25 mg, the reduced individual referencedose of ruxolitinib is, for example, 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5mg, 15 mg, 17.5 mg, 20 mg, 22.5 mg, including all integers and rangestherebetween. When the individual reference dose of ruxolitinib is 20mg, the reduced individual reference dose of ruxolitinib is, forexample, 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, or 17.5 mg,including all integers and ranges therebetween. When the individualreference dose of ruxolitinib is 15 mg, the reduced individual referencedose of ruxolitinib is, for example, 2.5 mg, 5 mg, 7.5 mg, 10 mg, or12.5 mg, including all integers and ranges therebetween. When theindividual reference dose of ruxolitinib is 10 mg, the reducedindividual reference dose of ruxolitinib is, for example, 2.5 mg, 5 mg,or 7.5 mg, including all integers and ranges therebetween. When theindividual reference dose of ruxolitinib is 5 mg, the reduced individualreference dose of ruxolitinib is, for example, 2.5 mg.

In some embodiments, the CYP3A4 substrate drug is sonidegib. The diseaseor condition treated with sonidegib can include any disease or conditiondescribed herein or for which sonidegib is indicated. For example, insome embodiments, sonidegib is indicated for treatment of adult patientswith locally advanced basal cell carcinoma (BCC) that has recurredfollowing surgery or radiation therapy, or those who are not candidatesfor surgery or radiation therapy. Sonidegib may be administered in a 200mg dosage form. In some embodiments, sonidegib is administered oncedaily up to a total daily dose of 200 mg. For example, when sonidegib isindicated for treatment of adult patients with locally advanced basalcell carcinoma (BCC) that has recurred following surgery or radiationtherapy, or those who are not candidates for surgery or radiationtherapy, the reference dose is 200 mg, administered once daily (totaldaily reference dose is 200 mg). Thus, in various embodiments, the totaldaily reference dose of sonidegib may be, for example, 25 mg, 50 mg, 100mg, 150 mg, or 200 mg. In accordance with certain embodiments of thepresent disclosure, when the total daily reference dose of sonidegib is,for example, 200 mg, the patient will take a reduced total daily dose ofsonidegib (either concomitantly with posaconazole or after a delayperiod after stopping posaconazole). In some embodiments, the reducedtotal daily dose of sonidegib is, for example, 25 mg, 50 mg, 100 mg, or150 mg, including all integers and ranges therebetween. When the totaldaily reference dose of sonidegib is 200 mg, the reduced total dailydose of sonidegib is, for example, 25 mg, 50 mg, 100 mg, or 150 mg,including all integers and ranges therebetween. Correspondingly, whenthe individual reference dose of sonidegib is 200 mg, the reducedindividual reference dose of sonidegib is, for example, 25 mg, 50 mg,100 mg, 150 mg, including all integers and ranges therebetween.

In some embodiments, the CYP3A4 substrate drug is sunitinib malate. Thedisease or condition treated with sunitinib malate can include anydisease or condition described herein or for which sunitinib malate isindicated. For example, in some embodiments, sunitinib malate isindicated for the treatment of gastrointestinal stromal tumor (GIST)after disease progression on or intolerance to imatinib mesylate. Insome embodiments, sunitinib malate is indicated for the treatment ofadvanced renal cell carcinoma (RCC). In some embodiments, sunitinibmalate is indicated for the adjuvant treatment of adult patients at highrisk of recurrent RCC following nephrectomy. In some embodiments,sunitinib malate is indicated for the treatment of progressive,well-differentiated pancreatic neuroendocrine tumors (pNET) in patientswith unresectable locally advanced or metastatic disease. Sunitinibmalate may be administered in a 12.5 mg, 25 mg, 37.5 mg, or 50 mg dosageform. In some embodiments, sunitinib malate is administered once dailyup to a total daily dose of 87.5 mg. In some embodiments, sunitinibmalate is administered once daily up to a total daily dose of 75 mg. Insome embodiments, sunitinib malate is administered once daily up to atotal daily dose of 62.5 mg. In some embodiments, sunitinib malate isadministered once daily up to a total daily dose of 50 mg. For example,when sunitinib malate is indicated for the treatment of gastrointestinalstromal tumor (GIST) after disease progression on or intolerance toimatinib mesylate, the reference dose is 50 mg, administered once daily(total daily reference dose is 50 mg) with or without food, for 4 weekson treatment followed by 2 weeks off. For example, when sunitinib malateis indicated for the treatment of advanced renal cell carcinoma (RCC),the reference dose is 50 mg, administered once daily (total dailyreference dose is 50 mg) with or without food, for 4 weeks on treatmentfollowed by 2 weeks off. For example, when sunitinib malate is indicatedfor the adjuvant treatment of adult patients at high risk of recurrentRCC following nephrectomy, the reference dose is 50 mg, administeredonce daily (total daily reference dose is 50 mg) with or without food,for 4 weeks on treatment followed by 2 weeks off for nine 6-week cycles.For example, when sunitinib malate is indicated for the treatment ofprogressive, well-differentiated pancreatic neuroendocrine tumors (pNET)in patients with unresectable locally advanced or metastatic disease,the reference dose is 37.5 mg, administered once daily (total dailyreference dose is 37.5 mg) with or without food, continuously without ascheduled off-treatment period. Dose interruptions and/or doseadjustments of 12.5 mg recommended based on individual safety andtolerability. Thus, in various embodiments, the total daily referencedose of sunitinib malate may be, for example, 5 mg, 12.5 mg, 25 mg, 37.5mg, 50 mg, 62.5 mg, 75 mg, or 87.5 mg, including all integers and rangestherebetween. In accordance with certain embodiments of the presentdisclosure, when the total daily reference dose of sunitinib malate is,for example, 87.5 mg, the patient will take a reduced total daily doseof sunitinib malate (either concomitantly with posaconazole or after adelay period after stopping posaconazole). In some embodiments, thereduced total daily dose of sunitinib malate is, for example, 5 mg, 12.5mg, 25 mg, 37.5 mg, 50 mg, 62.5 mg, or 75 mg, including all integers andranges therebetween. When the total daily reference dose of sunitinibmalate is 87.5 mg, the reduced total daily dose of sunitinib malate is,for example, 5 mg, 12.5 mg, 25 mg, 37.5 mg, 50 mg, 62.5 mg, or 75 mg,including all integers and ranges therebetween. When the total dailyreference dose of sunitinib malate is 50 mg, the reduced total dailydose of sunitinib malate is, for example, 5 mg, 12.5 mg, 25 mg or 37.5mg, including all integers and ranges therebetween. When the total dailyreference dose of sunitinib malate is 37.5 mg, the reduced total dailydose of sunitinib malate is, for example, 5 mg, 12.5 mg or 25 mg,including all integers and ranges therebetween. Correspondingly, whenthe individual reference dose of sunitinib malate is 50 mg, the reducedindividual reference dose of sunitinib malate is, for example, 5 mg,12.5 mg, 25 mg or 37.5 mg, including all integers and rangestherebetween. When the individual reference dose of sunitinib malate is37.5 mg, the reduced individual reference dose of sunitinib malate is,for example, 5 mg, 12.5 mg or 25 mg, including all integers and rangestherebetween. When the individual reference dose of sunitinib malate is25 mg, the reduced individual reference dose of sunitinib malate is, forexample, 5 mg or 12.5 mg, including all integers and rangestherebetween. When the individual reference dose of sunitinib malate is12.5 mg, the reduced individual reference dose of sunitinib malate is,for example, 5 mg.

In some embodiments, the CYP3A4 substrate drug is tofacitinib. Thedisease or condition treated with tofacitinib can include any disease orcondition described herein or for which tofacitinib is indicated. Forexample, in some embodiments, tofacitinib is indicated for the treatmentof adult patients with moderately to severely active rheumatoidarthritis who have had an inadequate response or intolerance tomethotrexate. It may be used as monotherapy or in combination withmethotrexate or other nonbiologic disease-modifying antirheumatic drugs(DMARDs). Use of tofacitinib in combination with biologic DMARDs orpotent immunosuppressants such as azathioprine and cyclosporine is notrecommended. In some embodiments, tofacitinib is indicated for thetreatment of adult patients with active psoriatic arthritis who have hadan inadequate response or intolerance to methotrexate or otherdisease-modifying antirheumatic drugs (DMARDs). Use of tofacitinib incombination with biologic DMARDs or potent immunosuppressants such asazathioprine and cyclosporine is not recommended. In some embodiments,tofacitinib is indicated for the treatment of adult patients withmoderately to severely active ulcerative colitis (UC). Limitations ofUse: Use of tofacitinib in combination with biological therapies for UCor with potent immunosuppressants such as azathioprine and cyclosporineis not recommended. Tofacitinib may be administered in a 5 mg, 10 mg, or11 mg dosage form. In some embodiments, tofacitinib is administeredtwice daily up to a total daily dose of 20 mg. In some embodiments,tofacitinib is administered twice daily up to a total daily dose of 10mg. In some embodiments, tofacitinib is administered once daily up to atotal daily dose of 11 mg. For example, when tofacitinib is indicatedfor the treatment of adult patients with moderately to severely activerheumatoid arthritis who have had an inadequate response or intoleranceto methotrexate, the reference dose is 5 mg, administered twice daily(total daily reference dose is 10 mg) or the reference dose is 11 mg,administered once daily (total daily reference dose is 11 mg).Recommended dosage in patients with moderate and severe renal impairmentor moderate hepatic impairment is tofacitinib 5 mg once daily. Forexample, when tofacitinib is indicated for the treatment of adultpatients with active psoriatic arthritis who have had an inadequateresponse or intolerance to methotrexate or other disease-modifyingantirheumatic drugs (DMARDs), the reference dose is 5 mg, administeredtwice daily (total daily reference dose is 10 mg) or the reference doseis 11 mg, administered once daily (total daily reference dose is 11 mg).Recommended dosage in patients with moderate and severe renal impairmentor moderate hepatic impairment is tofacitinib 5 mg once daily. Forexample, when tofacitinib is indicated for the treatment of adultpatients with moderately to severely active ulcerative colitis (UC), thereference dose is 10 mg, administered twice daily (total daily referencedose is 20 mg) for at least 8 weeks and then 5 or 10 mg twice daily.Discontinue after 16 weeks of 10 mg twice daily, if adequate therapeuticbenefit is not achieved. Use the lowest effective dose to maintainresponse. Recommended dosage in patients with moderate and severe renalimpairment or moderate hepatic impairment: half the total daily dosagerecommended for patients with normal renal and hepatic function. Thus,in various embodiments, the total daily reference dose of tofacitinibmay be, for example, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19mg, or 20 mg, including all integers and ranges therebetween. Inaccordance with certain embodiments of the present disclosure, when thetotal daily reference dose of tofacitinib is, for example, 20 mg, thepatient will take a reduced total daily dose of tofacitinib (eitherconcomitantly with posaconazole or after a delay period after stoppingposaconazole). In some embodiments, the reduced total daily dose oftofacitinib is, for example, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg,or 19 mg, including all integers and ranges therebetween. When the totaldaily reference dose of tofacitinib is 20 mg, the reduced total dailydose of tofacitinib is, for example, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg,7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17mg, 18 mg, or 19 mg, including all integers and ranges therebetween.When the total daily reference dose of tofacitinib is 11 mg, the reducedtotal daily dose of tofacitinib is, for example, 1 mg, 2 mg, 3 mg, 4 mg,5 mg, 6 mg, 7 mg, 8 mg, 9 mg, or 10 mg, including all integers andranges therebetween. When the total daily reference dose of tofacitinibis 10 mg, the reduced total daily dose of tofacitinib is, for example, 1mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, or 9 mg, including allintegers and ranges therebetween. Correspondingly, when the individualreference dose of tofacitinib is 11 mg, the reduced individual referencedose of tofacitinib is, for example, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg,7 mg, 8 mg, 9 mg, or 10 mg, including all integers and rangestherebetween. When the individual reference dose of tofacitinib is 10mg, the reduced individual reference dose of tofacitinib is, forexample, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, or 9 mg,including all integers and ranges therebetween. When the individualreference dose of tofacitinib is 5 mg, the reduced individual referencedose of tofacitinib is, for example, 1 mg, 2 mg, 3 mg, or 4 mg,including all integers and ranges therebetween.

In some embodiments, the CYP3A4 substrate drug is vemurafenib. Thedisease or condition treated with vemurafenib can include any disease orcondition described herein or for which vemurafenib is indicated. Forexample, in some embodiments, vemurafenib is indicated for the treatmentof patients with unresectable or metastatic melanoma with BRAF V600Emutation as detected by an FDA-approved test. In some embodiments,vemurafenib is indicated for the treatment of patients withErdheim-Chester Disease with BRAF V600 mutation. Vemurafenib may beadministered in a 240 mg dosage form. In some embodiments, vemurafenibis administered twice daily up to a total daily dose of 2000 mg. Forexample, when vemurafenib is indicated for the treatment of patientswith unresectable or metastatic melanoma with BRAF V600E mutation asdetected by an FDA-approved test, the reference dose is 960 mg,administered twice daily (total daily reference dose is 1920 mg)approximately 12 hours apart with or without a meal. For example, whenvemurafenib is indicated for the treatment of patients withErdheim-Chester Disease with BRAF V600 mutation, the reference dose is960 mg, administered twice daily (total daily reference dose is 1920 mg)approximately 12 hours apart with or without a meal. Thus, in variousembodiments, the total daily reference dose of vemurafenib may be, forexample, 120 mg, 240 mg, 360 mg, 480 mg, 600 mg, 720 mg, 840 mg, 960 mg,1080 mg, 1200 mg, 1320 mg, 1440 mg, 1560 mg, 1680 mg, 1800 mg, 1920 mg,or 2000 mg, including all integers and ranges therebetween. Inaccordance with certain embodiments of the present disclosure, when thetotal daily reference dose of vemurafenib is, for example, 2000 mg, thepatient will take a reduced total daily dose of vemurafenib (eitherconcomitantly with posaconazole or after a delay period after stoppingposaconazole). In some embodiments, the reduced total daily dose ofvemurafenib is, for example, 120 mg, 240 mg, 360 mg, 480 mg, 600 mg, 720mg, 840 mg, 960 mg, 1080 mg, 1200 mg, 1320 mg, 1440 mg, 1560 mg, 1680mg, or 1800 mg, or 1920, including all integers and ranges therebetween.When the total daily reference dose of vemurafenib is 2000 mg, thereduced total daily dose of vemurafenib is, for example, 120 mg, 240 mg,360 mg, 480 mg, 600 mg, 720 mg, 840 mg, 960 mg, 1080 mg, 1200 mg, 1320mg, 1440 mg, 1560 mg, 1680 mg, 1800 mg, or 1920 mg, including allintegers and ranges therebetween. When the total daily reference dose ofvemurafenib is 1920 mg, the reduced total daily dose of vemurafenib is,for example, 120 mg, 240 mg, 360 mg, 480 mg, 600 mg, 720 mg, 840 mg, 960mg, 1080 mg, 1200 mg, 1320 mg, 1440 mg, 1560 mg, 1680 mg, or 1800 mg,including all integers and ranges therebetween. Correspondingly, whenthe individual reference dose of vemurafenib is 240 mg, the reducedindividual reference dose of vemurafenib is, for example, 120 mg.

In some embodiments, the CYP3A4 substrate drug is venetoclax. Thedisease or condition treated with venetoclax can include any disease orcondition described herein or for which venetoclax is indicated. Forexample, in some embodiments, venetoclax is indicated for the treatmentof patients with chronic lymphocytic leukemia (CLL) or small lymphocyticlymphoma (SLL), with or without 17p deletion, who have received at leastone prior therapy. Venetoclax may be administered in a 10 mg, 50 mg, or100 mg dosage form. In some embodiments, venetoclax is administered oncedaily up to a total daily dose of 400 mg. For example, when venetoclaxis indicated for the treatment of patients with chronic lymphocyticleukemia (CLL) or small lymphocytic lymphoma (SLL), with or without 17pdeletion, who have received at least one prior therapy, the referencedose is 20 mg once daily for 7 days (total daily reference dose is 20mg), followed by a weekly ramp-up dosing schedule to the recommendeddaily dose of 400 mg, administered once daily (total daily referencedose is 400 mg). Thus, in various embodiments, the total daily referencedose of venetoclax may be, for example, 5 mg, 10 mg, 20 mg, 30 mg, 40mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg,140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg,230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg,320 mg, 330 mg, 340 mg, 350 mg, 360 mg, 370 mg, 380 mg, 390 mg, or 400mg, including all integers and ranges therebetween. In accordance withcertain embodiments of the present disclosure, when the total dailyreference dose of venetoclax is, for example, 400 mg, the patient willtake a reduced total daily dose of venetoclax (either concomitantly withposaconazole or after a delay period after stopping posaconazole). Insome embodiments, the reduced total daily dose of venetoclax is, forexample, 5 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg,90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg,180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg,270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, 350 mg,360 mg, 370 mg, 380 mg, or 390 mg, including all integers and rangesatherebetween. When the total daily reference dose of venetoclax is 400mg, the reduced total daily dose of venetoclax is, for example, 5 mg, 10mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290mg, 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, 350 mg, 360 mg, 370 mg, 380mg, or 390 mg, including all integers and ranges therebetween.Correspondingly, when the individual reference dose of venetoclax is 100mg, the reduced individual reference dose of venetoclax is, for example,5 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, or 90 mg,including all integers and ranges therebetween. When the individualreference dose of venetoclax is 50 mg, the reduced individual referencedose of venetoclax is, for example, 5 mg, 10 mg, 20 mg, 30 mg, or 40 mg,including all integers and ranges therebetween. When the individualreference dose of venetoclax is 20 mg, the reduced individual referencedose of venetoclax is, for example, 5 mg or 10 mg, including allintegers and ranges therebetween. When the individual reference dose ofvenetoclax is 10 mg, the reduced individual reference dose of venetoclaxis, for example, 5 mg.

In some embodiments, the time period for delaying treatment of theCYP3A4 substrate drug, or the time period during which the patient istreated with a reduced dose (e.g., no more than about 90%, about 75%,about 50%, about 25%, etc. of the reference dose) of the CYP3A4substrate, is at least about 1.5 times the reported average t_(1/2) ofposaconazole, e.g., about 2 times, about 2.5 times, about 3 times, about3.5 times, about 4 times, about 4.5 times, about 5 times, about 5.5times, about 6 times, about 6.5 times, about 7 times, about 7.5 times,about 8 times, about 8.5 times, about 9 times, about 9.5 times, about 10times, about 11 times, about 12 times, about 13 times, about 14 times,about 15 times, about 16 times, about 17 times, about 18 times, about 19times, about 20 times, about 21 times, about 22 times, about 23 times,about 24 times, about 25 times, about 26 times, about 27 times, about 28times, about 29 times, and about 30 times inclusive of all values andsubranges therebetween.

The present disclosure also provides methods for treating, orprescribing treatment, with a CYP3A4 substrate drug intended to treatany of the disorders or conditions described herein, to a patient whohas been administered posaconazole prior to the administration of theCYP3A4 substrate drug. In addition to treating the disorder or conditiontreatable with the CYP3A4 substrate drug, in some embodiments themethods of the present invention reduce the severity or incidence ofside effects associated with administration of the CYP3A4 substrate drugafter stopping administration of posaconazole. In embodiments, thesemethods include (a) treating a patient with multiple doses ofposaconazole, (b) not administering the CYP3A4 substrate drug during theadministration of the posaconazole regimen, (c) stopping administrationof posaconazole, (d) delaying treatment of a CYP3A4 substrate drug, orprescribing treatment of the CYP3A4 substrate drug to be delayed, for atleast 2-42 days after stopping the posaconazole regimen, and then (e)treating with a CYP3A4 substrate drug. In other embodiments, the methodsinclude (a) treating a patient with multiple doses of posaconazole, (b)not treating the patient with the CYP3A4 substrate drug during the theposaconazole regimen, (c) stopping the posaconazole regimen; and (d) forat least about 2-42 days after stopping the posaconazole regimen,treating the patient with the CYP3A4 substrate drug at a dose which isno more than about 50% of the reference dose of the CYP3A4 substratedrug (e.g., an amount in the range of about 10% to about 50%, or about10% to about 90%, of the reference dose, as described above). Thedisease or condition treated with the CYP3A4 substrate drug can includeany disease or condition described herein or for which CYP3 substratedrug is administered. In some embodiments, the disease or condition isselected from the group consisting of schizophrenia in adults andadolescents (13 to 17 years), depressive episodes associated withBipolar I Disorder (bipolar depression) in adults and pediatrics (10 to17 years) as monotherapy or as adjunctive therapy with lithium orvalproate, moderate bipolar depression, severe bipolar depression,severe bipolar depression with acute suicidal ideation and behavior(ASIB), chronic angina, erectile dysfunction (ED), benign prostatichyperplasia (BPH), and pulmonary arterial hypertension (PAH) (WHOGroup 1) to improve exercise ability. In other embodiments, the diseaseor condition is selected from the group consisting of non-small celllung cancer (NSCLC) whose disease has not progressed after four cyclesof platinum-based first-line chemotherapy, locally advanced ormetastatic NSCLC after failure of at least one prior chemotherapyregimen, locally advanced, unresectable or metastatic pancreatic cancer,overactive bladder with symptoms of urge urinary incontinence, urgency,and urinary frequency, advanced renal cell carcinoma (RCC) after failureof treatment with sunitinib or sorafenib, subependymal giant cellastrocytoma (SEGA) associated with tuberous sclerosis (TS) who requiretherapeutic intervention but are not candidates for curative surgicalresection, renal angiomyolipoma, and tuberous sclerosis complex. Inother embodiments, the disease or condition is selected from the groupconsisting of in combination with fulvestrant for the treatment of womenwith hormone receptor (HR)-positive, human epidermal growth factorreceptor 2 (HER2)-negative advanced or metastatic breast cancer withdisease progression following endocrine therapy, as monotherapy for thetreatment of adult patients with HRpositive, HER2-negative advanced ormetastatic breast cancer with disease progression following endocrinetherapy and prior chemotherapy in the metastatic setting, cysticfibrosis (CF) in patients age 2 years and older who have one mutation inthe CFTR gene that is responsive to ivacaftor based on clinical and/orin vitro assay data, deleterious or suspected deleterious germlineBRCA-mutated advanced ovarian cancer in adult patients who have beentreated with three or more prior lines of chemotherapy, intermediate orhigh-risk myelofibrosis, including primary myelofibrosis,post-polycythemia vera myelofibrosis and post-essential thrombocythemiamyelofibrosis, polycythemia vera patients who have had an inadequateresponse to or are intolerant of hydroxyurea, as an adjunctive therapyto antidepressants for the treatment of major depressive disorder (MDD),schizophrenia, cystic fibrosis (CF) patients aged 12 years and older whoare homozygous for the F508del mutation or who have at least onemutation in the cystic fibrosis transmembrane conductance regulator(CFTR) gene that is responsive to tezacaftor/ivacaftor based on in vitrodata and/or clinical evidence, metastatic colorectal cancer (CRC)patients who have been previously treated with fluoropyrimidine-,oxaliplatin- and irinotecan-based chemotherapy, an antiVEGF therapy,and, if RAS wild-type, an anti-EGFR therapy, locally advanced,unresectable or metastatic gastrointestinal stromal tumor (GIST)patients who have been previously treated with imatinib mesylate andsunitinib malate, hepatocellular carcinoma (HCC) who have beenpreviously treated with sorafenib, use with sofosbuvir, with or withoutribavirin, for the treatment of chronic HCV genotype 1 or 3 infection,metastatic non-small cell lung cancer (NSCLC) patients whose tumors areanaplastic lymphoma kinase (ALK) or ROS1-positive as detected by anFDA-approved test, opioid induced constipation (OIC) in adult patientswith chronic non-cancer pain, including patients with chronic painrelated to prior cancer or its treatment who do not require frequent(e.g., weekly) opioid dosage escalation, unresectable or metastaticmelanoma with BRAF V600E mutation as detected by an FDA-approved test,in combination with trametinib, for the treatment of patients withunresectable or metastatic melanoma with BRAF V600E or V600K mutationsas detected by an FDA-approved test, adjuvant treatment of patients withmelanoma with BRAF V600E or V600K mutations, as detected by anFDA-approved test, and involvement of lymph node(s), following completeresection, metastatic non-small cell lung cancer (NSCLC) with BRAF V600Emutation as detected by an FDA-approved test, locally advanced ormetastatic anaplastic thyroid cancer (ATC) in patients with BRAF V600Emutation and with no satisfactory locoregional treatment options, withor without ribavirin for treatment of chronic HCV genotypes 1 or 4infection in adults, the treatment of patients with non-metastaticcastration-resistant prostate cancer, the treatment of patients withanaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lungcancer (NSCLC) who have progressed on or are intolerant to crizotinib,the treatment of seizures associated with Lennox-Gastaut syndrome orDravet syndrome in patients 2 years of age and older, the treatment ofadult patients with relapsed follicular lymphoma (FL) who have receivedat least two prior systemic therapies, the treatment of adult patientswith relapsed or refractory chronic lymphocytic leukemia (CLL) or smalllymphocytic lymphoma (SLL) after at least two prior therapies, thetreatment of adult patients with relapsed or refractory follicularlymphoma (FL) after at least two prior systemic therapies, incombination with binimetinib, for the treatment of patients withunresectable or metastatic melanoma with a BRAF V600E or V600K mutation,as detected by an FDA-approved test, the treatment of premenopausalwomen with acquired, generalized hypoactive sexual desire disorder(HSDD) as characterized by low sexual desire that causes marked distressor interpersonal difficulty and is not due to a co-existing medical orpsychiatric condition, problems within the relationship, or the effectsof a medication or other drug substance, to reduce the risk ofhospitalization for worsening heart failure in patients with stable,symptomatic chronic heart failure with left ventricular ejectionfraction ≤35%, who are in sinus rhythm with resting heart rate ≥70 beatsper minute and either are on maximally tolerated doses of beta-blockersor have a contraindication to beta-blocker use, the treatment of adultpatients with relapsed or refractory acute myeloid leukemia (AML) with asusceptible IDH1 mutation as detected by an FDA-approved test, thetreatment of patients with multiple myeloma who have received at least 2prior regimens, including bortezomib and an immunomodulatory agent, thetreatment of adult patients with locally advanced basal cell carcinoma(BCC) that has recurred following surgery or radiation therapy, or thosewho are not candidates for surgery or radiation therapy, the treatmentof patients with unresectable or metastatic melanoma with BRAF V600Emutation as detected by an FDA-approved test, and the treatment ofpatients with Erdheim-Chester Disease with BRAF V600 mutation. In someembodiments, the time period for delaying administration of the CYP3A4substrate drug, or the time period during which the CYP3A4 substratedrug is administered at no more than 50% of the reference dose, isgreater than about 21 days, such as 22, 23, 24, 25, 26, 27, 28, 29, 30,31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, or 45 days,e.g., for patients with one or more physiological characteristicsdescribed herein.

INCORPORATION BY REFERENCE

The entire contents of each of U.S. application Ser. No. 15/596,585,filed May 16, 2017; U.S. application Ser. No. 15/670,262, filed Aug. 7,2017; U.S. application Ser. No. 15/670,267, filed Aug. 7, 2017; U.S.application Ser. No. 15/670,268, filed Aug. 7, 2017; U.S. applicationSer. No. 15/670,271, filed Aug. 7, 2017; U.S. application Ser. No.15/036,678, filed Jul. 16, 2018, are hereby incorporated by referencefor all purposes.

Other particular embodiments are provided herein below:

Embodiments I

1. A method of treating a patient who has previously been administered atherapeutically effective regimen of posaconazole, with a CYP3A4substrate drug contraindicated for concomitant administration with astrong CYP3A4 inhibitor, said method comprising:

first treating the patient, or prescribing a first treatment to begin,with the CYP3A4 substrate drug at least 2-42 days after stoppingadministration of posaconazole.

2. The method of embodiment 1, wherein said CYP3A4 substrate drug isselected from the group consisting of lurasidone, ranolazine,lumacaftor/ivacaftor, venetoclax, trabectedin, ribociclib succinate,deflazacort, cinacalcet hydrochloride, pimavanserin tartrate,aripiprazole lauroxil, cariprazine hydrochloride, simeprevir sodium,everolimus, saxagliptin hydrochloride, saxagliptin/metforminhydrochloride, ticagrelor, vilazodone hydrochloride, apixaban,tofacitinib citrate, eletriptan hydrobromide, nilotinib hydrochloridemonohydrate, dronedarone hydrochloride, fluticasonepropionate/salmeterol xinafoate, rivaroxaban, tadalafil, ibrutinib,cobimetinib, colchicine, cabazitaxel, tolvaptan, fosaprepitantdimeglumine, aprepitant, solifenacin succinate, erlotinib hydrochloride,ado-trastuzumab ematansine, bosutinib monohydrate, sunitinib malate,fesoterodine fumarate, maraviroc, pazopanib hydrochloride, aripiprazole,axitinib, dapagliflozin/saxagliptin, cabozantinib S-malate, ponatinibhydrochloride, isavuconazonium sulfate, lomitapide mesylate,iloperidone, palbociclib, levomilnacipran hydrochloride, pimozide,pomalidomide, abemaciclib, ivacaftor, ruxolitinib phosphate,brexpiprazole, ivacaftor/tezacaftor, regorafenib, daclatasvir,crizotinib, naloxegol oxalate, dabrafenib, olaparib, elbasvir andgrazoprevir, apalutamide, brigatinib, cannabidiol, copanlisib,duvelisib, encorafenib, flibanserin, ivabradine, ivosidenib,panobinostat, sonidegib, and vemurafenib.

3. The method of embodiment 2, wherein the CYP3A4 substrate drug islurasidone.

4. The method of embodiment 2, wherein the CYP3A4 substrate drug isranolazine.

5. The method of embodiment 2, wherein the CYP3A4 substrate drug istadalafil.

6. The method of any of embodiments 1-5, wherein the patient is obese.

7. The method of embodiment 6, wherein the patient has at least one ofthe following characteristics:

i) BMI of at least about 35;

ii) % IBW of at least about 150%;

iii) waist size greater than about 42 inches;

iv) % body fat greater than about 40%;

v) total body fat greater than about 40 kg; and

vi) medically diagnosed as obese.

8. The method of any of embodiments 1-7, wherein the CYP3A4 substratedrug is ranolazine, and the AUC of ranolazine is maintained at a levelof no more than about 150% of a normal baseline AUC of ranolazine.

9. The method of any of embodiments 1-7, wherein the CYP3A4 substratedrug is ranolazine, and the C_(max) of ranolazine is maintained at alevel of no more than about 150% of a normal baseline C_(max) ofranolazine.

10. The method of any of embodiments 1-7, wherein the CYP3A4 substratedrug is lurasidone, and the AUC of lurasidone is maintained at a levelof no more than about 216% of a normal baseline AUC of lurasidone.

11. The method of any of embodiments 1-7, wherein the CYP3A4 substratedrug is lurasidone, and the C_(max) of lurasidone is maintained at alevel of no more than about 210% of a normal baseline C_(max) oflurasidone.

12. The method of any of embodiments 1-7, wherein the CYP3A4 substratedrug is tadalafil, and the AUC of tadalafil is maintained at a level ofno more than about 410% of a normal baseline AUC of tadalafil.

13. The method of any of embodiments 1-7, wherein the CYP3A4 substratedrug is tadalafil, and the a Cmax of tadalafil is maintained at a levelof no more than about 120% of a normal baseline Cmax of tadalafil.

14. The method of embodiments 1-10, wherein the patient is a poor orintermediate CYP3A4 metabolizer.

15. A method of treating a patient with a CYP3A4 substrate drugcontraindicated for concomitant administration with a strong CYP3A4inhibitor, comprising:

treating or prescribing a therapeutically effective amount of a CYP3A4substrate drug to a patient in need thereof,

wherein:

said patient has previously been administered a therapeuticallyeffective regimen of posaconazole, and

for at least about 2-42 days after discontinuation of the posaconazoleregimen, said patient is treated with the CYP3A4 substrate drug is at adose which is no more than about 50% of the reference dose.

16. The method of embodiment 15, wherein said CYP3A4 substrate drug isselected from the group consisting of lurasidone, ranolazine,lumacaftor/ivacaftor, venetoclax, trabectedin, ribociclib succinate,deflazacort, cinacalcet hydrochloride, pimavanserin tartrate,aripiprazole lauroxil, cariprazine hydrochloride, simeprevir sodium,everolimus, saxagliptin hydrochloride, saxagliptin/metforminhydrochloride, ticagrelor, vilazodone hydrochloride, apixaban,tofacitinib citrate, eletriptan hydrobromide, nilotinib hydrochloridemonohydrate, dronedarone hydrochloride, fluticasonepropionate/salmeterol xinafoate, rivaroxaban, tadalafil, ibrutinib,cobimetinib, colchicine, cabazitaxel, tolvaptan, fosaprepitantdimeglumine, aprepitant, solifenacin succinate, erlotinib hydrochloride,ado-trastuzumab ematansine, bosutinib monohydrate, sunitinib malate,fesoterodine fumarate, maraviroc, pazopanib hydrochloride, aripiprazole,axitinib, dapagliflozin/saxagliptin, cabozantinib S-malate, ponatinibhydrochloride, isavuconazonium sulfate, lomitapide mesylate,iloperidone, palbociclib, levomilnacipran hydrochloride, pimozide,pomalidomide, abemaciclib, ivacaftor, ruxolitinib phosphate,brexpiprazole, ivacaftor/tezacaftor, regorafenib, daclatasvir,crizotinib, naloxegol oxalate, dabrafenib, olaparib, elbasvir andgrazoprevir, apalutamide, brigatinib, cannabidiol, copanlisib,duvelisib, encorafenib, flibanserin, ivabradine, ivosidenib,panobinostat, sonidegib, and vemurafenib.

17. The method of embodiment 16, wherein the CYP3A4 substrate drug islurasidone.

18. The method of embodiment 16, wherein the CYP3A4 substrate drug isranolazine.

19. The method of embodiment 16, wherein the CYP3A4 substrate drug istadalafil.

20. The method of any of embodiments 15-19, wherein the patient isobese.

21. The method of embodiment 20, wherein the patient has at least one ofthe following characteristics:

i) BMI of at least about 35;

ii) % IBW of at least about 150%;

iii) waist size greater than about 42 inches;

iv) % body fat greater than about 40%;

v) total body fat greater than about 40 kg; and

vi) medically diagnosed as obese.

22. The method of any of embodiments 15-21, wherein the CYP3A4 substratedrug is ranolazine, and the AUC of ranolazine is maintained at a levelof no more than about a normal baseline AUC of ranolazine to about 150%of the normal baseline AUC of ranolazine.

23. The method of any of embodiments 15-21, wherein the CYP3A4 substratedrug is ranolazine, and the C_(max) of ranolazine is maintained at alevel of no more than about a normal baseline C_(max) of ranolazine toabout 150% of the normal baseline C_(max) of ranolazine.

24. The method of any of embodiments 15-21, wherein the CYP3A4 substratedrug is lurasidone, and the AUC of lurasidone is maintained at a levelof no more than about a normal baseline AUC of lurasidone to about 216%of the normal baseline AUC of lurasidone.

25. The method of any of embodiments 15-21, wherein the CYP3A4 substratedrug is lurasidone, and the C_(max) of lurasidone is maintained at alevel of no more than about a normal baseline C_(max) of lurasidone toabout 210% of the normal baseline C_(max) of lurasidone.

26. The method of any of embodiments 15-21, wherein the CYP3A4 substratedrug is tadalafil, and the AUC of tadalafil is maintained at a level ofno more than about 410% of a normal baseline AUC of tadalafil.

27. The method of any of embodiments 15-21, wherein the CYP3A4 substratedrug is tadalafil, and the a Cmax of tadalafil is maintained at a levelof no more than about 120% of a normal baseline Cmax of tadalafil.

28. The method of embodiments 15-27, wherein the patient is a poor orintermediate CYP3A4 metabolizer.

29. The method of embodiment 15, wherein the CYP3A4 substrate drug isranolazine and the daily dose is no more than about 500 mg for at leastabout 2-42 days after discontinuation of the posaconazole regimen.

30. A method of treating a disease or condition in a patient with aCYP3A4 substrate drug which is contraindicated for concomitant use witha strong CYP3A4 inhibitor, wherein the patient is also in need oftreatment with posaconazole, comprising:

(a) treating a patient with a therapeutically effective regimen ofposaconazole;

(b) not treating the patient with the CYP3A4 substrate drug during theposaconazole regimen, and for at least 2-42 days after stopping theposaconazole regimen; and then

(c) treating, or prescribing treatment to begin, with a therapeuticallyeffective amount of the CYP3A4 substrate drug;

wherein the disease or condition treated with the CYP3A4 substrate drugis selected from the group consisting of schizophrenia in adults andadolescents (13 to 17 years), depressive episodes associated withBipolar I Disorder (bipolar depression) in adults and pediatrics (10 to17 years) as monotherapy or as adjunctive therapy with lithium orvalproate, moderate bipolar depression, severe bipolar depression,severe bipolar depression with acute suicidal ideation and behavior(ASIB), chronic angina, cystic fibrosis in patients 6 years and olderwho are homozygous for the F508del mutation in the CFTR gene, chroniclymphocytic leukemia in patients with with 17p deletion, who havereceived at least one prior therapy, unresectable or metastaticliposarcoma or leiomyosarcoma in patients who received a prioranthracycline-containing regimen, advanced or metastatic breast cancerin postmenopausal women with hormone receptor (HR)-positive, humanepidermal growth factor receptor 2 (HER2)-negative advanced ormetastatic breast cancer, negative advanced or metastatic breast cancerin combination with an aromatase inhibitor for postmenopausal women,Duchenne muscular dystrophy (DMD), secondary hyperparathyroidism (HPT)in patients with chronic kidney disease (CKD) on dialysis, hypercalcemiain patients with parathyroid carcinoma or in patients with primary HPTfor who parathyroidectomy would be indicated on the basis of serumcalcium levels, but who are unable to undergo parathyroidectomy,hallucinations and delusions associated with Parkinson's diseasepsychosis, schizophrenia, acute manic or mixed episodes associated withbipolar I disorder, chronic hepatitis C (CHC) infection as a componentof a combination antiviral treatment regimen with peginterferon alfa andribavirin in HCV genotype 1 infected subjects with compensated liverdisease, postmenopausal women with advanced hormone receptor-positive,HER2-negative breast cancer (advanced HR+BC), e.g., in combination withexemestane after failure of treatment with letrozole or anastrozole,progressive neuroendocrine tumors of pancreatic origin (PNET),progressive, well-differentiated, non-functional neuroendocrine tumors(NET) of gastrointestinal (GI) or lung origin that are unresectable,locally advanced or metastatic, advanced renal cell carcinoma (RCC),e.g., after failure of treatment with sunitinib or sorafenib, renalangiomyolipoma and tuberous sclerosis complex (TSC), not requiringimmediate surgery, TSC in patients who have subependymal giant cellastrocytoma (SEGA) that require therapeutic intervention but are notcandidates for surgical resection, type 2 diabetes mellitus in adults asan adjunct to diet and exercise to improve glycemic control, majordepressive disorder (MDD), thrombotic cardiovascular events (e.g.,cardiovascular death, myocardial infarction, or stroke) in patients withacute coronary syndrome (ACS), stroke and systemic embolism in patientswith nonvalvular atrial fibrillation, deep vein thrombosis (DVT), whichmay lead to pulmonary embolism (PE) in patients who have undergone hipor knee replacement surgery, DVT, PE, recurrent DVT and PE followinginitial therapy, moderate to severe active rheumatoid arthritis inpatients who have had inadequate response or tolerance to methotrexate,acute migraine with or without aura, chronic phase and accelerated phasePhiladelphia chromosome positive chronic myeloid leukemia (Ph+ CML) innewly diagnosed patients or in patients resistant to or intolerant toprior therapy that included imatinib, atrial fibrillation (AF) inpatients with a history of paroxysmal or persistant AF or atrial flutter(AFK), who are in sinus rhythm or will be cardioverted, asthma inpatients aged 4 years and older, airflow obstruction and reducingexacerbations in patients with chronic obstructive pulmonary disease,erectile dysfunction (ED), benign prostatic hyperplasia (BPH), pulmonaryarterial hypertension (PAH) (WHO Group 1) to improve exercise ability,gout flares, Familial Mediterranean fever antiretroviral therapy,anxiety disorders, panic disorders, seizures, insomnia, hypertension,cardiovascular disease, hyperlipidemia, cancer, such as primary kidneycancer, advanced primary liver cancer, radioactive iodine resistantadvanced thyroid carcinoma, renal cell carcinoma, imatinib-resistantgastrointestinal stromal tumor, mantle cell lymphoma in patients whohave received at least one prior therapy, chronic lymphocyticleukemia/small lymphocytic lymphoma, chronic lymphocytic leukemia/smalllymphocytic lymphoma with 17p deletion, Waldenström's macroglobulinemia,marginal zone lymphoma who require systemic therapy and have received atleast one prior anti-CD20-based therapy, unresectable or metastaticmelanoma with a BRAF V600E or V600K mutation, allergies,transplantation, hormone-refractory metastatic prostate cancerpreviously treated with a docetaxel-containing treatment regimen,hormone-refractory metastatic prostate cancer previously treated with adocetaxel-containing treatment regimen, treatment of clinicallysignificant hypervolemic and euvolemic hyponatremia, including patientswith heart failure and Syndrome of Inappropriate Antidiuretic Hormone(SIADH), prevention of acute and delayed nausea and vomiting associatedwith initial and repeat courses of highly emetogenic cancer chemotherapy(HEC) including high-dose cisplatin, prevention of delayed nausea andvomiting associated with initial and repeat courses of moderatelyemetogenic cancer chemotherapy (MEC), over-active bladder with symptomsof urge urinary incontinence, urgency, and urinary frequency, metastaticnon-small cell lung cancer (NSCLC) whose tumors have epidermal growthfactor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitutionmutations as detected by an FDA-approved test receiving first-line,maintenance, or second or greater line treatment after progression,locally advanced, unresectable or metastatic pancreatic cancer, incombination with gemcitabine, HER2-positive, metastatic breast cancerwho previously received trastuzumab and a taxane, separately or incombination in patients who have either: received prior therapy formetastatic disease or developed disease recurrence during or within sixmonths of completing adjuvant therapy, chronic, accelerated, or blastphase Ph+ chronic myelogenous leukemia (CML) in adults with resistanceor intolerance to prior therapy, gastrointestinal stromal tumor (GIST)after disease progression on or intolerance to imatinib mesylate,advanced renal cell carcinoma (RCC), progressive, well-differentiatedpancreatic neuroendocrine tumors (pNET) in patients with unresectablelocally advanced or metastatic disease, CCR5-tropic HIV-1 infection inpatients 2 years of age and older weighing at least 10 kg in combinationwith other antiretroviral agents, advanced renal cell carcinoma,advanced soft tissue sarcoma who have received prior chemotherapy, manicand mixed episodes associated with Bipolar I, Major Depressive Disorder,irritability associated with Autistic Disorder, Tourette's disorder,agitation associated with schizophrenia or bipolar mania, advanced renalcell carcinoma after failure of one prior systemic therapy, to improveglycemic control in adults with type 2 diabetes mellitus (T2DM) who haveinadequate control with dapagliflozin or who are already treated withdapagliflozin and saxagliptin, progressive, metastatic medullary thyroidcancer (MTC), advanced renal cell carcinoma (RCC) who have receivedprior anti-angiogenic therapy, chronic phase, accelerated phase, orblast phase chronic myeloid leukemia (CML) or Ph+ ALL in adults for whomno other tyrosine kinase inhibitor (TKI) therapy is indicated,T315I-positive CML (chronic phase, accelerated phase, or blast phase) orT315I-positive Philadelphia chromosome in adults, positive acutelymphoblastic leukemia (Ph+ ALL), invasive aspergillosis, invasivemucormycosis, to reduce low-density lipoprotein cholesterol (LDL-C),total cholesterol (TC), apolipoprotein B (apo B), and non-high densitylipoprotein cholesterol (non-HDL-C) in patients with homozygous familialhypercholesterolemia (HoFH), schizophrenia in adults, hormone receptor(HR)-positive, human epidermal growth factor receptor 2 (HER2)-negativeadvanced or metastatic breast cancer in combination with an aromataseinhibitor as initial endocrine based therapy in postmenopausal women, orfulvestrant in women with disease progression following endocrinetherapy, Major Depressive Disorder (MDD), suppression of motor andphonic tics in patients with Tourette's Disorder who have failed torespond satisfactorily to standard treatment, treatment of multiplemyeloma in patients who have received at least two prior therapiesincluding lenalidomide and a proteasome inhibitor and have demonstrateddisease progression on or within 60 days of completion of the lasttherapy, non-small cell lung cancer (NSCLC) whose disease has notprogressed after four cycles of platinum-based first-line chemotherapy,locally advanced or metastatic NSCLC after failure of at least one priorchemotherapy regimen, locally advanced, unresectable or metastaticpancreatic cancer, overactive bladder with symptoms of urge urinaryincontinence, urgency, and urinary frequency, advanced renal cellcarcinoma (RCC) after failure of treatment with sunitinib or sorafenib,subependymal giant cell astrocytoma (SEGA) associated with tuberoussclerosis (TS) who require therapeutic intervention but are notcandidates for curative surgical resection, renal angiomyolipoma,tuberous sclerosis complex, in combination with fulvestrant for thetreatment of women with hormone receptor (HR)-positive, human epidermalgrowth factor receptor 2 (HER2)-negative advanced or metastatic breastcancer with disease progression following endocrine therapy, asmonotherapy for the treatment of adult patients with HRpositive,HER2-negative advanced or metastatic breast cancer with diseaseprogression following endocrine therapy and prior chemotherapy in themetastatic setting, cystic fibrosis (CF) in patients age 2 years andolder who have one mutation in the CFTR gene that is responsive toivacaftor based on clinical and/or in vitro assay data, deleterious orsuspected deleterious germline BRCA-mutated advanced ovarian cancer inadult patients who have been treated with three or more prior lines ofchemotherapy, intermediate or high-risk myelofibrosis, including primarymyelofibrosis, post-polycythemia vera myelofibrosis and post-essentialthrombocythemia myelofibrosis, polycythemia vera patients who have hadan inadequate response to or are intolerant of hydroxyurea, as anadjunctive therapy to antidepressants for the treatment of majordepressive disorder (MDD), schizophrenia, cystic fibrosis (CF) patientsaged 12 years and older who are homozygous for the F508del mutation orwho have at least one mutation in the cystic fibrosis transmembraneconductance regulator (CFTR) gene that is responsive totezacaftor/ivacaftor based on in vitro data and/or clinical evidence,metastatic colorectal cancer (CRC) patients who have been previouslytreated with fluoropyrimidine-, oxaliplatin- and irinotecan-basedchemotherapy, an antiVEGF therapy, and, if RAS wild-type, an anti-EGFRtherapy, locally advanced, unresectable or metastatic gastrointestinalstromal tumor (GIST) patients who have been previously treated withimatinib mesylate and sunitinib malate, hepatocellular carcinoma (HCC)who have been previously treated with sorafenib, use with sofosbuvir,with or without ribavirin, for the treatment of chronic HCV genotype 1or 3 infection, metastatic non-small cell lung cancer (NSCLC) patientswhose tumors are anaplastic lymphoma kinase (ALK) or ROS1-positive asdetected by an FDA-approved test, opioid induced constipation (OIC) inadult patients with chronic non-cancer pain, including patients withchronic pain related to prior cancer or its treatment who do not requirefrequent (e.g., weekly) opioid dosage escalation, unresectable ormetastatic melanoma with BRAF V600E mutation as detected by anFDA-approved test, in combination with trametinib, for the treatment ofpatients with unresectable or metastatic melanoma with BRAF V600E orV600K mutations as detected by an FDA-approved test, adjuvant treatmentof patients with melanoma with BRAF V600E or V600K mutations, asdetected by an FDA-approved test, and involvement of lymph node(s),following complete resection, metastatic non-small cell lung cancer(NSCLC) with BRAF V600E mutation as detected by an FDA-approved test,locally advanced or metastatic anaplastic thyroid cancer (ATC) inpatients with BRAF V600E mutation and with no satisfactory locoregionaltreatment options, with or without ribavirin for treatment of chronicHCV genotypes 1 or 4 infection in adults, the treatment of patients withnon-metastatic castration-resistant prostate cancer, the treatment ofpatients with anaplastic lymphoma kinase (ALK)-positive metastaticnon-small cell lung cancer (NSCLC) who have progressed on or areintolerant to crizotinib, the treatment of seizures associated withLennox-Gastaut syndrome or Dravet syndrome in patients 2 years of ageand older, the treatment of adult patients with relapsed follicularlymphoma (FL) who have received at least two prior systemic therapies,the treatment of adult patients with relapsed or refractory chroniclymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) after atleast two prior therapies, the treatment of adult patients with relapsedor refractory follicular lymphoma (FL) after at least two prior systemictherapies, in combination with binimetinib, for the treatment ofpatients with unresectable or metastatic melanoma with a BRAF V600E orV600K mutation, as detected by an FDA-approved test, the treatment ofpremenopausal women with acquired, generalized hypoactive sexual desiredisorder (HSDD) as characterized by low sexual desire that causes markeddistress or interpersonal difficulty and is not due to a co-existingmedical or psychiatric condition, problems within the relationship, orthe effects of a medication or other drug substance, to reduce the riskof hospitalization for worsening heart failure in patients with stable,symptomatic chronic heart failure with left ventricular ejectionfraction ≤35%, who are in sinus rhythm with resting heart rate ≥70 beatsper minute and either are on maximally tolerated doses of beta-blockersor have a contraindication to beta-blocker use, the treatment of adultpatients with relapsed or refractory acute myeloid leukemia (AML) with asusceptible IDH1 mutation as detected by an FDA-approved test, thetreatment of patients with multiple myeloma who have received at least 2prior regimens, including bortezomib and an immunomodulatory agent, thetreatment of adult patients with locally advanced basal cell carcinoma(BCC) that has recurred following surgery or radiation therapy, or thosewho are not candidates for surgery or radiation therapy, the treatmentof patients with unresectable or metastatic melanoma with BRAF V600Emutation as detected by an FDA-approved test, and the treatment ofpatients with Erdheim-Chester Disease with BRAF V600 mutation.

31. The method of embodiment 30, wherein said CYP3A4 substrate drug isselected from the group consisting of lurasidone, ranolazine,lumacaftor/ivacaftor, venetoclax, trabectedin, ribociclib succinate,deflazacort, cinacalcet hydrochloride, pimavanserin tartrate,aripiprazole lauroxil, cariprazine hydrochloride, simeprevir sodium,everolimus, saxagliptin hydrochloride, saxagliptin/metforminhydrochloride, ticagrelor, vilazodone hydrochloride, apixaban,tofacitinib citrate, eletriptan hydrobromide, nilotinib hydrochloridemonohydrate, dronedarone hydrochloride, fluticasonepropionate/salmeterol xinafoate, rivaroxaban, tadalafil, ibrutinib,cobimetinib, colchicine, cabazitaxel, tolvaptan, fosaprepitantdimeglumine, aprepitant, solifenacin succinate, erlotinib hydrochloride,ado-trastuzumab ematansine, bosutinib monohydrate, sunitinib malate,fesoterodine fumarate, maraviroc, pazopanib hydrochloride, aripiprazole,axitinib, dapagliflozin/saxagliptin, cabozantinib S-malate, ponatinibhydrochloride, isavuconazonium sulfate, lomitapide mesylate,iloperidone, palbociclib, levomilnacipran hydrochloride, pimozide,pomalidomide, abemaciclib, ivacaftor, ruxolitinib phosphate,brexpiprazole, ivacaftor/tezacaftor, regorafenib, daclatasvir,crizotinib, naloxegol oxalate, dabrafenib, olaparib, elbasvir andgrazoprevir, apalutamide, brigatinib, cannabidiol, copanlisib,duvelisib, encorafenib, flibanserin, ivabradine, ivosidenib,panobinostat, sonidegib, and vemurafenib.

32. The method of embodiment 31, wherein the CYP3A4 substrate drug islurasidone.

33. The method of embodiment 31, wherein the CYP3A4 substrate drug isranolazine.

34. The method of embodiment 31, wherein the CYP3A4 substrate drug istadalafil.

35. The method of any of embodiments 30-34, wherein the patient isobese.

36. The method of embodiment 35, wherein the patient has at least one ofthe following characteristics:

i) BMI of at least about 35;

ii) % IBW of at least about 150%;

iii) waist size greater than about 42 inches;

iv) % body fat greater than about 40%;

v) total body fat greater than about 40 kg; and

vi) medically diagnosed as obese.

37. The method of any of embodiments 30-36, wherein the CYP3A4 substratedrug is ranolazine, and the AUC of ranolazine is maintained at a levelof no more than about 150% of a normal baseline AUC of ranolazine.

38. The method of any of embodiments 30-36, wherein the CYP3A4 substratedrug is ranolazine, and the C_(max) of ranolazine is maintained at alevel of no more than about 150% of a normal baseline C_(max) ofranolazine.

39. The method of any of embodiments 30-36, wherein the CYP3A4 substratedrug is lurasidone, and the AUC of lurasidone is maintained at a levelof no more than about 216% of a normal baseline AUC of lurasidone.

40. The method of any of embodiments 30-36, wherein the CYP3A4 substratedrug is lurasidone, and the C_(max) of lurasidone is maintained at alevel of no more than about 210% of a normal baseline C_(max) oflurasidone.

41. The method of any of embodiments 30-36, wherein the CYP3A4 substratedrug is tadalafil, and the AUC of tadalafil is maintained at a level ofno more than about 410% of a normal baseline AUC of tadalafil.

42. The method of any of embodiments 30-36, wherein the CYP3A4 substratedrug is tadalafil, and the a Cmax of tadalafil is maintained at a levelof no more than about 120% of a normal baseline Cmax of tadalafil.

43. The method of any of embodiments 30-42, wherein the patient is apoor or intermediate CYP3A4 metabolizer.

44. A method of treating a disease or condition in a patient with aCYP3A4 substrate drug which is contraindicated for concomitant use witha strong CYP3A4 inhibitor, wherein the patient is also in need oftreatment with posaconazole, comprising:

(a) treating a patient with a therapeutically effective regimen ofposaconazole to the patient;

(b) not administering the CYP3A4 substrate drug during theadministration of the posaconazole regimen;

(c) for at least about 2-42 days after stopping the posaconazoleregimen, treating the patient with, or prescribing, the CYP3A4 substratedrug at a dose which is no more than about 50% of the reference dose;

wherein the disease or condition treated with the CYP3A4 substrate drugis selected from the group consisting of schizophrenia in adults andadolescents (13 to 17 years), depressive episodes associated withBipolar I Disorder (bipolar depression) in adults and pediatrics (10 to17 years) as monotherapy or as adjunctive therapy with lithium orvalproate, moderate bipolar depression, severe bipolar depression,severe bipolar depression with acute suicidal ideation and behavior(ASIB), chronic angina, cystic fibrosis in patients 6 years and olderwho are homozygous for the F508del mutation in the CFTR gene, chroniclymphocytic leukemia in patients with 17p deletion, who have received atleast one prior therapy, unresectable or metastatic liposarcoma orleiomyosarcoma in patients who received a prior anthracycline-containingregimen, advanced or metastatic breast cancer in postmenopausal womenwith hormone receptor (HR)-positive, human epidermal growth factorreceptor 2 (HER2)-negative advanced or metastatic breast cancer,negative advanced or metastatic breast cancer in combination with anaromatase inhibitor for postmenopausal women, Duchenne musculardystrophy (DMD), secondary hyperparathyroidism (HPT) in patients withchronic kidney disease (CKD) on dialysis, hypercalcemia in patients withparathyroid carcinoma or in patients with primary HPT for whoparathyroidectomy would be indicated on the basis of serum calciumlevels, but who are unable to undergo parathyroidectomy, hallucinationsand delusions associated with Parkinson's disease psychosis,schizophrenia, acute manic or mixed episodes associated with bipolar Idisorder, chronic hepatitis C (CHC) infection as a component of acombination antiviral treatment regimen with peginterferon alfa andribavirin in HCV genotype 1 infected subjects with compensated liverdisease, postmenopausal women with advanced hormone receptor-positive,HER2-negative breast cancer (advanced HR+BC), e.g., in combination withexemestane after failure of treatment with letrozole or anastrozole,progressive neuroendocrine tumors of pancreatic origin (PNET),progressive, well-differentiated, non-functional neuroendocrine tumors(NET) of gastrointestinal (GI) or lung origin that are unresectable,locally advanced or metastatic, advanced renal cell carcinoma (RCC),e.g., after failure of treatment with sunitinib or sorafenib, renalangiomyolipoma and tuberous sclerosis complex (TSC), not requiringimmediate surgery, TSC in patients who have subependymal giant cellastrocytoma (SEGA) that require therapeutic intervention but are notcandidates for surgical resection, type 2 diabetes mellitus in adults asan adjunct to diet and exercise to improve glycemic control, majordepressive disorder (MDD), thrombotic cardiovascular events (e.g.,cardiovascular death, myocardial infarction, or stroke) in patients withacute coronary syndrome (ACS), stroke and systemic embolism in patientswith nonvalvular atrial fibrillation, deep vein thrombosis (DVT), whichmay lead to pulmonary embolism (PE) in patients who have undergone hipor knee replacement surgery, DVT, PE, recurrent DVT and PE followinginitial therapy, moderate to severe active rheumatoid arthritis inpatients who have had inadequate response or tolerance to methotrexate,acute migraine with or without aura, chronic phase and accelerated phasePhiladelphia chromosome positive chronic myeloid leukemia (Ph+ CML) innewly diagnosed patients or in patients resistant to or intolerant toprior therapy that included imatinib, atrial fibrillation (AF) inpatients with a history of paroxysmal or persistant AF or atrial flutter(AFK), who are in sinus rhythm or will be cardioverted, asthma inpatients aged 4 years and older, airflow obstruction and reducingexacerbations in patients with chronic obstructive pulmonary disease,erectile dysfunction (ED), benign prostatic hyperplasia (BPH), pulmonaryarterial hypertension (PAH) (WHO Group 1) to improve exercise ability,gout flares, Familial Mediterranean fever antiretroviral therapy,anxiety disorders, panic disorders, seizures, insomnia, hypertension,cardiovascular disease, hyperlipidemia, cancer, such as primary kidneycancer, advanced primary liver cancer, radioactive iodine resistantadvanced thyroid carcinoma, renal cell carcinoma, imatinib-resistantgastrointestinal stromal tumor, mantle cell lymphoma in patients whohave received at least one prior therapy, chronic lymphocyticleukemia/small lymphocytic lymphoma, chronic lymphocytic leukemia/smalllymphocytic lymphoma with 17p deletion, Waldenström's macroglobulinemia,marginal zone lymphoma who require systemic therapy and have received atleast one prior anti-CD20-based therapy, unresectable or metastaticmelanoma with a BRAF V600E or V600K mutation, allergies,transplantation, hormone-refractory metastatic prostate cancerpreviously treated with a docetaxel-containing treatment regimen,hormone-refractory metastatic prostate cancer previously treated with adocetaxel-containing treatment regimen, treatment of clinicallysignificant hypervolemic and euvolemic hyponatremia, including patientswith heart failure and Syndrome of Inappropriate Antidiuretic Hormone(SIADH), prevention of acute and delayed nausea and vomiting associatedwith initial and repeat courses of highly emetogenic cancer chemotherapy(HEC) including high-dose cisplatin, prevention of delayed nausea andvomiting associated with initial and repeat courses of moderatelyemetogenic cancer chemotherapy (MEC), over-active bladder with symptomsof urge urinary incontinence, urgency, and urinary frequency, metastaticnon-small cell lung cancer (NSCLC) whose tumors have epidermal growthfactor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitutionmutations as detected by an FDA-approved test receiving first-line,maintenance, or second or greater line treatment after progression,locally advanced, unresectable or metastatic pancreatic cancer, incombination with gemcitabine, HER2-positive, metastatic breast cancerwho previously received trastuzumab and a taxane, separately or incombination in patients who have either: received prior therapy formetastatic disease or developed disease recurrence during or within sixmonths of completing adjuvant therapy, chronic, accelerated, or blastphase Ph+ chronic myelogenous leukemia (CML) in adults with resistanceor intolerance to prior therapy, gastrointestinal stromal tumor (GIST)after disease progression on or intolerance to imatinib mesylate,advanced renal cell carcinoma (RCC), progressive, well-differentiatedpancreatic neuroendocrine tumors (pNET) in patients with unresectablelocally advanced or metastatic disease, CCR5-tropic HIV-1 infection inpatients 2 years of age and older weighing at least 10 kg in combinationwith other antiretroviral agents, advanced renal cell carcinoma,advanced soft tissue sarcoma who have received prior chemotherapy, manicand mixed episodes associated with Bipolar I, Major Depressive Disorder,irritability associated with Autistic Disorder, Tourette's disorder,agitation associated with schizophrenia or bipolar mania, advanced renalcell carcinoma after failure of one prior systemic therapy, to improveglycemic control in adults with type 2 diabetes mellitus (T2DM) who haveinadequate control with dapagliflozin or who are already treated withdapagliflozin and saxagliptin, progressive, metastatic medullary thyroidcancer (MTC), advanced renal cell carcinoma (RCC) who have receivedprior anti-angiogenic therapy, chronic phase, accelerated phase, orblast phase chronic myeloid leukemia (CML) or Ph+ ALL in adults for whomno other tyrosine kinase inhibitor (TKI) therapy is indicated,T315I-positive CML (chronic phase, accelerated phase, or blast phase) orT315I-positive Philadelphia chromosome in adults, positive acutelymphoblastic leukemia (Ph+ ALL), invasive aspergillosis, invasivemucormycosis, to reduce low-density lipoprotein cholesterol (LDL-C),total cholesterol (TC), apolipoprotein B (apo B), and non-high densitylipoprotein cholesterol (non-HDL-C) in patients with homozygous familialhypercholesterolemia (HoFH), schizophrenia in adults, hormone receptor(HR)-positive, human epidermal growth factor receptor 2 (HER2)-negativeadvanced or metastatic breast cancer in combination with an aromataseinhibitor as initial endocrine based therapy in postmenopausal women, orfulvestrant in women with disease progression following endocrinetherapy, Major Depressive Disorder (MDD), suppression of motor andphonic tics in patients with Tourette's Disorder who have failed torespond satisfactorily to standard treatment, treatment of multiplemyeloma in patients who have received at least two prior therapiesincluding lenalidomide and a proteasome inhibitor and have demonstrateddisease progression on or within 60 days of completion of the lasttherapy, non-small cell lung cancer (NSCLC) whose disease has notprogressed after four cycles of platinum-based first-line chemotherapy,locally advanced or metastatic NSCLC after failure of at least one priorchemotherapy regimen, locally advanced, unresectable or metastaticpancreatic cancer, overactive bladder with symptoms of urge urinaryincontinence, urgency, and urinary frequency, advanced renal cellcarcinoma (RCC) after failure of treatment with sunitinib or sorafenib,subependymal giant cell astrocytoma (SEGA) associated with tuberoussclerosis (TS) who require therapeutic intervention but are notcandidates for curative surgical resection, renal angiomyolipoma,tuberous sclerosis complex, in combination with fulvestrant for thetreatment of women with hormone receptor (HR)-positive, human epidermalgrowth factor receptor 2 (HER2)-negative advanced or metastatic breastcancer with disease progression following endocrine therapy, asmonotherapy for the treatment of adult patients with HRpositive,HER2-negative advanced or metastatic breast cancer with diseaseprogression following endocrine therapy and prior chemotherapy in themetastatic setting, cystic fibrosis (CF) in patients age 2 years andolder who have one mutation in the CFTR gene that is responsive toivacaftor based on clinical and/or in vitro assay data, deleterious orsuspected deleterious germline BRCA-mutated advanced ovarian cancer inadult patients who have been treated with three or more prior lines ofchemotherapy, intermediate or high-risk myelofibrosis, including primarymyelofibrosis, post-polycythemia vera myelofibrosis and post-essentialthrombocythemia myelofibrosis, polycythemia vera patients who have hadan inadequate response to or are intolerant of hydroxyurea, as anadjunctive therapy to antidepressants for the treatment of majordepressive disorder (MDD), schizophrenia, cystic fibrosis (CF) patientsaged 12 years and older who are homozygous for the F508del mutation orwho have at least one mutation in the cystic fibrosis transmembraneconductance regulator (CFTR) gene that is responsive totezacaftor/ivacaftor based on in vitro data and/or clinical evidence,metastatic colorectal cancer (CRC) patients who have been previouslytreated with fluoropyrimidine-, oxaliplatin- and irinotecan-basedchemotherapy, an antiVEGF therapy, and, if RAS wild-type, an anti-EGFRtherapy, locally advanced, unresectable or metastatic gastrointestinalstromal tumor (GIST) patients who have been previously treated withimatinib mesylate and sunitinib malate, hepatocellular carcinoma (HCC)who have been previously treated with sorafenib, use with sofosbuvir,with or without ribavirin, for the treatment of chronic HCV genotype 1or 3 infection, metastatic non-small cell lung cancer (NSCLC) patientswhose tumors are anaplastic lymphoma kinase (ALK) or ROS1-positive asdetected by an FDA-approved test, opioid induced constipation (OIC) inadult patients with chronic non-cancer pain, including patients withchronic pain related to prior cancer or its treatment who do not requirefrequent (e.g., weekly) opioid dosage escalation, unresectable ormetastatic melanoma with BRAF V600E mutation as detected by anFDA-approved test, in combination with trametinib, for the treatment ofpatients with unresectable or metastatic melanoma with BRAF V600E orV600K mutations as detected by an FDA-approved test, adjuvant treatmentof patients with melanoma with BRAF V600E or V600K mutations, asdetected by an FDA-approved test, and involvement of lymph node(s),following complete resection, metastatic non-small cell lung cancer(NSCLC) with BRAF V600E mutation as detected by an FDA-approved test,locally advanced or metastatic anaplastic thyroid cancer (ATC) inpatients with BRAF V600E mutation and with no satisfactory locoregionaltreatment options, with or without ribavirin for treatment of chronicHCV genotypes 1 or 4 infection in adults, the treatment of patients withnon-metastatic castration-resistant prostate cancer, the treatment ofpatients with anaplastic lymphoma kinase (ALK)-positive metastaticnon-small cell lung cancer (NSCLC) who have progressed on or areintolerant to crizotinib, the treatment of seizures associated withLennox-Gastaut syndrome or Dravet syndrome in patients 2 years of ageand older, the treatment of adult patients with relapsed follicularlymphoma (FL) who have received at least two prior systemic therapies,the treatment of adult patients with relapsed or refractory chroniclymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) after atleast two prior therapies, the treatment of adult patients with relapsedor refractory follicular lymphoma (FL) after at least two prior systemictherapies, in combination with binimetinib, for the treatment ofpatients with unresectable or metastatic melanoma with a BRAF V600E orV600K mutation, as detected by an FDA-approved test, the treatment ofpremenopausal women with acquired, generalized hypoactive sexual desiredisorder (HSDD) as characterized by low sexual desire that causes markeddistress or interpersonal difficulty and is not due to a co-existingmedical or psychiatric condition, problems within the relationship, orthe effects of a medication or other drug substance, to reduce the riskof hospitalization for worsening heart failure in patients with stable,symptomatic chronic heart failure with left ventricular ejectionfraction ≤35%, who are in sinus rhythm with resting heart rate ≥70 beatsper minute and either are on maximally tolerated doses of beta-blockersor have a contraindication to beta-blocker use, the treatment of adultpatients with relapsed or refractory acute myeloid leukemia (AML) with asusceptible IDH1 mutation as detected by an FDA-approved test, thetreatment of patients with multiple myeloma who have received at least 2prior regimens, including bortezomib and an immunomodulatory agent, thetreatment of adult patients with locally advanced basal cell carcinoma(BCC) that has recurred following surgery or radiation therapy, or thosewho are not candidates for surgery or radiation therapy, the treatmentof patients with unresectable or metastatic melanoma with BRAF V600Emutation as detected by an FDA-approved test, and the treatment ofpatients with Erdheim-Chester Disease with BRAF V600 mutation.

45. The method of embodiment 44, wherein said CYP3A4 substrate drug isselected from the group consisting of lurasidone, ranolazine,lumacaftor/ivacaftor, venetoclax, trabectedin, ribociclib succinate,deflazacort, cinacalcet hydrochloride, pimavanserin tartrate,aripiprazole lauroxil, cariprazine hydrochloride, simeprevir sodium,everolimus, saxagliptin hydrochloride, saxagliptin/metforminhydrochloride, ticagrelor, vilazodone hydrochloride, apixaban,tofacitinib citrate, eletriptan hydrobromide, nilotinib hydrochloridemonohydrate, dronedarone hydrochloride, fluticasonepropionate/salmeterol xinafoate, rivaroxaban, tadalafil, ibrutinib,cobimetinib, colchicine, cabazitaxel, tolvaptan, fosaprepitantdimeglumine, aprepitant, solifenacin succinate, erlotinib hydrochloride,ado-trastuzumab ematansine, bosutinib monohydrate, sunitinib malate,fesoterodine fumarate, maraviroc, pazopanib hydrochloride, aripiprazole,axitinib, dapagliflozin/saxagliptin, cabozantinib S-malate, ponatinibhydrochloride, isavuconazonium sulfate, lomitapide mesylate,iloperidone, palbociclib, levomilnacipran hydrochloride, pimozide,pomalidomide, abemaciclib, ivacaftor, ruxolitinib phosphate,brexpiprazole, ivacaftor/tezacaftor, regorafenib, daclatasvir,crizotinib, naloxegol oxalate, dabrafenib, olaparib, elbasvir andgrazoprevir, apalutamide, brigatinib, cannabidiol, copanlisib,duvelisib, encorafenib, flibanserin, ivabradine, ivosidenib,panobinostat, sonidegib, and vemurafenib.

46. The method of embodiment 45, wherein the CYP3A4 substrate drug islurasidone.

47. The method of embodiment 45, wherein the CYP3A4 substrate drug isranolazine.

48. The method of embodiment 45, wherein the CYP3A4 substrate drug istadalafil.

49. The method of any of embodiments 44-48, wherein the patient isobese.

50. The method of embodiment 49, wherein the patient has at least one ofthe following characteristics:

i) BMI of at least about 35;

ii) % IBW of at least about 150%;

iii) waist size greater than about 42 inches;

iv) % body fat greater than about 40%;

v) total body fat greater than about 40 kg; and

vi) medically diagnosed as obese.

51. The method of any of embodiments 44-50, wherein the CYP3A4 substratedrug is ranolazine, and the AUC of ranolazine is maintained at a levelof no more than about a normal baseline AUC of ranolazine to about 150%of the normal baseline AUC of ranolazine.

52. The method of any of embodiments 44-50, wherein the CYP3A4 substratedrug is ranolazine, and the C_(max) of ranolazine is maintained at alevel of no more than about a normal baseline C_(max) of ranolazine toabout 150% of the normal baseline C_(max) of ranolazine.

53. The method of any of embodiments 44-50, wherein the CYP3A4 substratedrug is lurasidone, and the AUC of lurasidone is maintained at a levelof no more than about a normal baseline AUC of lurasidone to about 216%of the normal baseline AUC of lurasidone.

54. The method of any of embodiments 44-50, wherein the CYP3A4 substratedrug is lurasidone, and the C_(max) of lurasidone is maintained at alevel of no more than about a normal baseline C_(max) of lurasidone toabout 210% of the normal baseline C_(max) of lurasidone.

55. The method of any of embodiments 44-50, wherein the CYP3A4 substratedrug is tadalafil, and the AUC of tadalafil is maintained at a level ofno more than about 410% of a normal baseline AUC of tadalafil.

56. The method of any of embodiments 44-50, wherein the CYP3A4 substratedrug is tadalafil, and the a Cmax of tadalafil is maintained at a levelof no more than about 120% of a normal baseline Cmax of tadalafil.

57. The method of embodiments 44-56, wherein the patient is a poor orintermediate CYP3A4 metabolizer.

58. The method of embodiment 44, wherein the CYP3A4 substrate drug isranolazine and the daily dose is no more than about 500 mg for at leastabout 2-42 days after discontinuation of the posaconazole regimen.

59. A method of treating a patient in need thereof comprising delaying afirst treatment of a CYP3A4 substrate drug until about 2-42 days afterstopping administration of posaconazole.

60. The method of embodiment 59, wherein said CYP3A4 substrate drug isselected from the group consisting of lurasidone, ranolazine,lumacaftor/ivacaftor, venetoclax, trabectedin, ribociclib succinate,deflazacort, cinacalcet hydrochloride, pimavanserin tartrate,aripiprazole lauroxil, cariprazine hydrochloride, simeprevir sodium,everolimus, saxagliptin hydrochloride, saxagliptin/metforminhydrochloride, ticagrelor, vilazodone hydrochloride, apixaban,tofacitinib citrate, eletriptan hydrobromide, nilotinib hydrochloridemonohydrate, dronedarone hydrochloride, fluticasonepropionate/salmeterol xinafoate, rivaroxaban, tadalafil, ibrutinib,cobimetinib, colchicine, cabazitaxel, tolvaptan, fosaprepitantdimeglumine, aprepitant, solifenacin succinate, erlotinib hydrochloride,ado-trastuzumab ematansine, bosutinib monohydrate, sunitinib malate,fesoterodine fumarate, maraviroc, pazopanib hydrochloride, aripiprazole,axitinib, dapagliflozin/saxagliptin, cabozantinib S-malate, ponatinibhydrochloride, isavuconazonium sulfate, lomitapide mesylate,iloperidone, palbociclib, levomilnacipran hydrochloride, pimozide,pomalidomide, abemaciclib, ivacaftor, ruxolitinib phosphate,brexpiprazole, ivacaftor/tezacaftor, regorafenib, daclatasvir,crizotinib, naloxegol oxalate, dabrafenib, olaparib, elbasvir andgrazoprevir, apalutamide, brigatinib, cannabidiol, copanlisib,duvelisib, encorafenib, flibanserin, ivabradine, ivosidenib,panobinostat, sonidegib, and vemurafenib.

61. The method of embodiment 60, wherein the CYP3A4 substrate drug islurasidone.

62. The method of embodiment 60, wherein the CYP3A4 substrate drug isranolazine.

63. The method of embodiment 60, wherein the CYP3A4 substrate drug istadalafil.

64. The method of any of embodiments 59-63, wherein the patient isobese.

65. The method of embodiment 64, wherein the patient has at least one ofthe following characteristics:

i) BMI of at least about 35;

ii) % IBW of at least about 150%;

iii) waist size greater than about 42 inches;

iv) % body fat greater than about 40%;

v) total body fat greater than about 40 kg; and

vi) medically diagnosed as obese.

66. The method of any of embodiments 59-65, wherein the CYP3A4 substratedrug is ranolazine, and the AUC of ranolazine is maintained at a levelof no more than about 150% of a normal baseline AUC of ranolazine.

67. The method of any of embodiments 59-65, wherein the CYP3A4 substratedrug is ranolazine, and the C_(max) of ranolazine is maintained at alevel of no more than about 150% of a normal baseline C_(max) ofranolazine.

68. The method of any of embodiments 59-65, wherein the CYP3A4 substratedrug is lurasidone, and the AUC of lurasidone is maintained at a levelof no more than about 216% of a normal baseline AUC of lurasidone.

68. The method of any of embodiments 59-65, wherein the CYP3A4 substratedrug is lurasidone, and the C_(max) of lurasidone is maintained at alevel of no more than about 210% of a normal baseline C_(max) oflurasidone.

69. The method of any of embodiments 59-65, wherein the CYP3A4 substratedrug is tadalafil, and the AUC of tadalafil is maintained at a level ofno more than about 410% of a normal baseline AUC of tadalafil.

70. The method of any of embodiments 59-65, wherein the CYP3A4 substratedrug is tadalafil, and the a Cmax of tadalafil is maintained at a levelof no more than about 120% of a normal baseline Cmax of tadalafil.

80. The method of embodiments 59-70, wherein the patient is a poor orintermediate CYP3A4 metabolizer.

81. A method of treating a patient previously on posaconazole with aCYP3A4 substrate drug which is contraindicated for concomitant use witha strong CYP3A4 inhibitor comprising, delaying a first treatment, orprescribing a first treatment to be delayed, of the CYP3A4 substratedrug for at least about 2-42 days after posaconazole administration hasceased.

82. The method of embodiment 81, wherein said CYP3A4 substrate drug isselected from the group consisting of lurasidone, ranolazine,lumacaftor/ivacaftor, venetoclax, trabectedin, ribociclib succinate,deflazacort, cinacalcet hydrochloride, pimavanserin tartrate,aripiprazole lauroxil, cariprazine hydrochloride, simeprevir sodium,everolimus, saxagliptin hydrochloride, saxagliptin/metforminhydrochloride, ticagrelor, vilazodone hydrochloride, apixaban,tofacitinib citrate, eletriptan hydrobromide, nilotinib hydrochloridemonohydrate, dronedarone hydrochloride, fluticasonepropionate/salmeterol xinafoate, rivaroxaban, tadalafil, ibrutinib,cobimetinib, colchicine, cabazitaxel, tolvaptan, fosaprepitantdimeglumine, aprepitant, solifenacin succinate, erlotinib hydrochloride,ado-trastuzumab ematansine, bosutinib monohydrate, sunitinib malate,fesoterodine fumarate, maraviroc, pazopanib hydrochloride, aripiprazole,axitinib, dapagliflozin/saxagliptin, cabozantinib S-malate, ponatinibhydrochloride, isavuconazonium sulfate, lomitapide mesylate,iloperidone, palbociclib, levomilnacipran hydrochloride, pimozide,pomalidomide, abemaciclib, ivacaftor, ruxolitinib phosphate,brexpiprazole, ivacaftor/tezacaftor, regorafenib, daclatasvir,crizotinib, naloxegol oxalate, dabrafenib, olaparib, elbasvir andgrazoprevir, apalutamide, brigatinib, cannabidiol, copanlisib,duvelisib, encorafenib, flibanserin, ivabradine, ivosidenib,panobinostat, sonidegib, and vemurafenib.

83. The method of embodiment 82, wherein the CYP3A4 substrate drug islurasidone.

84. The method of embodiment 82, wherein the CYP3A4 substrate drug isranolazine.

85. The method of embodiment 45, wherein the CYP3A4 substrate drug istadalafil.

86. The method of any of embodiments 81-85, wherein the patient isobese.

87. The method of embodiment 86, wherein the patient has at least one ofthe following characteristics:

i) BMI of at least about 35;

ii) % IBW of at least about 150%;

iii) waist size greater than about 42 inches;

iv) % body fat greater than about 40%;

v) total body fat greater than about 40 kg; and

vi) medically diagnosed as obese.

88. The method of any of embodiments 81-87, wherein the CYP3A4 substratedrug is ranolazine, and the AUC of ranolazine is maintained at a levelof no more than about 150% of a normal baseline AUC of ranolazine.

89. The method of any of embodiments 81-87, wherein the CYP3A4 substratedrug is ranolazine, and the C_(max) of ranolazine is maintained at alevel of no more than about 150% of a normal baseline C_(max) ofranolazine.

90. The method of any of embodiments 81-87, wherein the CYP3A4 substratedrug is lurasidone, and the AUC of lurasidone is maintained at a levelof no more than about 216% of a normal baseline AUC of lurasidone.

91. The method of any of embodiments 81-87, wherein the CYP3A4 substratedrug is lurasidone, and the C_(max) of lurasidone is maintained at alevel of no more than about 210% of a normal baseline C_(max) oflurasidone.

92. The method of any of embodiments 81-87, wherein the CYP3A4 substratedrug is tadalafil, and the AUC of tadalafil is maintained at a level ofno more than about 410% of a normal baseline AUC of tadalafil.

93. The method of any of embodiments 81-87, wherein the CYP3A4 substratedrug is tadalafil, and the a Cmax of tadalafil is maintained at a levelof no more than about 120% of a normal baseline Cmax of tadalafil.

94. The method of embodiments 81-93, wherein the patient is a poor orintermediate CYP3A4 metabolizer.

95. A method of treating a patient with a CYP3A4 substrate drugcontraindicated for concomitant use with a strong CYP3A4 inhibitor,comprising treating the patient, or prescribing a treatment of, theCYP3A4 substrate drug at a dose which is less than or equal to about 50%of the reference dose for a period of at least about 2-42 days afterstopping administration of posaconazole.

96. The method of embodiment 95, wherein said CYP3A4 substrate drug isselected from the group consisting of lurasidone, ranolazine,lumacaftor/ivacaftor, venetoclax, trabectedin, ribociclib succinate,deflazacort, cinacalcet hydrochloride, pimavanserin tartrate,aripiprazole lauroxil, cariprazine hydrochloride, simeprevir sodium,everolimus, saxagliptin hydrochloride, saxagliptin/metforminhydrochloride, ticagrelor, vilazodone hydrochloride, apixaban,tofacitinib citrate, eletriptan hydrobromide, nilotinib hydrochloridemonohydrate, dronedarone hydrochloride, fluticasonepropionate/salmeterol xinafoate, rivaroxaban, tadalafil, ibrutinib,cobimetinib, colchicine, cabazitaxel, tolvaptan, fosaprepitantdimeglumine, aprepitant, solifenacin succinate, erlotinib hydrochloride,ado-trastuzumab ematansine, bosutinib monohydrate, sunitinib malate,fesoterodine fumarate, maraviroc, pazopanib hydrochloride, aripiprazole,axitinib, dapagliflozin/saxagliptin, cabozantinib S-malate, ponatinibhydrochloride, isavuconazonium sulfate, lomitapide mesylate,iloperidone, palbociclib, levomilnacipran hydrochloride, pimozide,pomalidomide, abemaciclib, ivacaftor, ruxolitinib phosphate,brexpiprazole, ivacaftor/tezacaftor, regorafenib, daclatasvir,crizotinib, naloxegol oxalate, dabrafenib, olaparib, elbasvir andgrazoprevir, apalutamide, brigatinib, cannabidiol, copanlisib,duvelisib, encorafenib, flibanserin, ivabradine, ivosidenib,panobinostat, sonidegib, and vemurafenib.

97. The method of embodiment 96, wherein the CYP3A4 substrate drug islurasidone.

98. The method of embodiment 96, wherein the CYP3A4 substrate drug isranolazine.

99. The method of embodiment 96, wherein the CYP3A4 substrate drug istadalafil.

100. The method of any of embodiments 95-99, wherein the patient isobese.

101. The method of embodiment 100, wherein the patient has at least oneof the following characteristics:

i) BMI of at least about 35;

ii) % IBW of at least about 150%;

iii) waist size greater than about 42 inches;

iv) % body fat greater than about 40%;

v) total body fat greater than about 40 kg; and

vi) medically diagnosed as obese.

102. The method of any of embodiments 95-101, wherein the CYP3A4substrate drug is ranolazine, and the AUC of ranolazine is maintained ata level of no more than about a normal baseline AUC of ranolazine toabout 150% of the normal baseline AUC of ranolazine.

103. The method of any of embodiments 95-101, wherein the CYP3A4substrate drug is ranolazine, and the C_(max) of ranolazine ismaintained at a level of no more than about a normal baseline C_(max) ofranolazine to about 150% of the normal baseline C_(max) of ranolazine.

104. The method of any of embodiments 95-101, wherein the CYP3A4substrate drug is lurasidone, and the AUC of lurasidone is maintained ata level of no more than about a normal baseline AUC of lurasidone toabout 216% of the normal baseline AUC of lurasidone.

105. The method of any of embodiments 95-101, wherein the CYP3A4substrate drug is lurasidone, and the C_(max) of lurasidone ismaintained at a level of no more than about a normal baseline C_(max) oflurasidone to about 210% of the normal baseline C_(max) of lurasidone.

106. The method of any of embodiments 95-101, wherein the CYP3A4substrate drug is tadalafil, and the AUC of tadalafil is maintained at alevel of no more than about 410% of a normal baseline AUC of tadalafil.

107. The method of any of embodiments 95-101, wherein the CYP3A4substrate drug is tadalafil, and the a Cmax of tadalafil is maintainedat a level of no more than about 120% of a normal baseline Cmax oftadalafil.

108. The method of embodiments 95-107, wherein the patient is a poor orintermediate CYP3A4 metabolizer.

109. The method of embodiment 95, wherein the CYP3A4 substrate drug isranolazine and the daily dose is no more than about 500 mg for at leastabout 2-42 days after discontinuation of the posaconazole regimen.

110. A method of treating a disease or condition in a patient with aCYP3A4 substrate drug which is contraindicated for concomitant use witha strong CYP3A4 inhibitor, comprising:

(a) delaying a first treatment, or prescribing a delay of the firsttreatment, of the CYP3A4 substrate drug for at least 2-42 days afterstopping administration of posaconazole; and then(b) administering the CYP3A4 substrate drug;

wherein the disease or condition treated with the CYP3A4 substrate drugis selected from the group consisting of schizophrenia in adults andadolescents (13 to 17 years), depressive episodes associated withBipolar I Disorder (bipolar depression) in adults and pediatrics (10 to17 years) as monotherapy or as adjunctive therapy with lithium orvalproate, moderate bipolar depression, severe bipolar depression,severe bipolar depression with acute suicidal ideation and behavior(ASIB), chronic angina, cystic fibrosis in patients 6 years and olderwho are homozygous for the F508del mutation in the CFTR gene, chroniclymphocytic leukemia in patients with 17p deletion, who have received atleast one prior therapy, unresectable or metastatic liposarcoma orleiomyosarcoma in patients who received a prior anthracycline-containingregimen, advanced or metastatic breast cancer in postmenopausal womenwith hormone receptor (HR)-positive, human epidermal growth factorreceptor 2 (HER2)-negative advanced or metastatic breast cancer,negative advanced or metastatic breast cancer in combination with anaromatase inhibitor for postmenopausal women, Duchenne musculardystrophy (DMD), secondary hyperparathyroidism (HPT) in patients withchronic kidney disease (CKD) on dialysis, hypercalcemia in patients withparathyroid carcinoma or in patients with primary HPT for whoparathyroidectomy would be indicated on the basis of serum calciumlevels, but who are unable to undergo parathyroidectomy, hallucinationsand delusions associated with Parkinson's disease psychosis,schizophrenia, acute manic or mixed episodes associated with bipolar Idisorder, chronic hepatitis C (CHC) infection as a component of acombination antiviral treatment regimen with peginterferon alfa andribavirin in HCV genotype 1 infected subjects with compensated liverdisease, postmenopausal women with advanced hormone receptor-positive,HER2-negative breast cancer (advanced HR+BC), e.g., in combination withexemestane after failure of treatment with letrozole or anastrozole,progressive neuroendocrine tumors of pancreatic origin (PNET),progressive, well-differentiated, non-functional neuroendocrine tumors(NET) of gastrointestinal (GI) or lung origin that are unresectable,locally advanced or metastatic, advanced renal cell carcinoma (RCC),e.g., after failure of treatment with sunitinib or sorafenib, renalangiomyolipoma and tuberous sclerosis complex (TSC), not requiringimmediate surgery, TSC in patients who have subependymal giant cellastrocytoma (SEGA) that require therapeutic intervention but are notcandidates for surgical resection, type 2 diabetes mellitus in adults asan adjunct to diet and exercise to improve glycemic control, majordepressive disorder (MDD), thrombotic cardiovascular events (e.g.,cardiovascular death, myocardial infarction, or stroke) in patients withacute coronary syndrome (ACS), stroke and systemic embolism in patientswith nonvalvular atrial fibrillation, deep vein thrombosis (DVT), whichmay lead to pulmonary embolism (PE) in patients who have undergone hipor knee replacement surgery, DVT, PE, recurrent DVT and PE followinginitial therapy, moderate to severe active rheumatoid arthritis inpatients who have had inadequate response or tolerance to methotrexate,acute migraine with or without aura, chronic phase and accelerated phasePhiladelphia chromosome positive chronic myeloid leukemia (Ph+ CML) innewly diagnosed patients or in patients resistant to or intolerant toprior therapy that included imatinib, atrial fibrillation (AF) inpatients with a history of paroxysmal or persistant AF or atrial flutter(AFK), who are in sinus rhythm or will be cardioverted, asthma inpatients aged 4 years and older, airflow obstruction and reducingexacerbations in patients with chronic obstructive pulmonary disease,erectile dysfunction (ED), benign prostatic hyperplasia (BPH), pulmonaryarterial hypertension (PAH) (WHO Group 1) to improve exercise ability,gout flares, Familial Mediterranean fever, antiretroviral therapy,anxiety disorders, panic disorders, seizures, insomnia, hypertension,cardiovascular disease, hyperlipidemia, cancer, such as primary kidneycancer, advanced primary liver cancer, radioactive iodine resistantadvanced thyroid carcinoma, renal cell carcinoma, imatinib-resistantgastrointestinal stromal tumor, mantle cell lymphoma in patients whohave received at least one prior therapy, chronic lymphocyticleukemia/small lymphocytic lymphoma, chronic lymphocytic leukemia/smalllymphocytic lymphoma with 17p deletion, Waldenström's macroglobulinemia,marginal zone lymphoma who require systemic therapy and have received atleast one prior anti-CD20-based therapy, unresectable or metastaticmelanoma with a BRAF V600E or V600K mutation, allergies,transplantation, hormone-refractory metastatic prostate cancerpreviously treated with a docetaxel-containing treatment regimen,hormone-refractory metastatic prostate cancer previously treated with adocetaxel-containing treatment regimen, treatment of clinicallysignificant hypervolemic and euvolemic hyponatremia, including patientswith heart failure and Syndrome of Inappropriate Antidiuretic Hormone(SIADH), prevention of acute and delayed nausea and vomiting associatedwith initial and repeat courses of highly emetogenic cancer chemotherapy(HEC) including high-dose cisplatin, prevention of delayed nausea andvomiting associated with initial and repeat courses of moderatelyemetogenic cancer chemotherapy (MEC), over-active bladder with symptomsof urge urinary incontinence, urgency, and urinary frequency, metastaticnon-small cell lung cancer (NSCLC) whose tumors have epidermal growthfactor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitutionmutations as detected by an FDA-approved test receiving first-line,maintenance, or second or greater line treatment after progression,locally advanced, unresectable or metastatic pancreatic cancer, incombination with gemcitabine, HER2-positive, metastatic breast cancerwho previously received trastuzumab and a taxane, separately or incombination in patients who have either: received prior therapy formetastatic disease or developed disease recurrence during or within sixmonths of completing adjuvant therapy, chronic, accelerated, or blastphase Ph+ chronic myelogenous leukemia (CML) in adults with resistanceor intolerance to prior therapy, gastrointestinal stromal tumor (GIST)after disease progression on or intolerance to imatinib mesylate,advanced renal cell carcinoma (RCC), progressive, well-differentiatedpancreatic neuroendocrine tumors (pNET) in patients with unresectablelocally advanced or metastatic disease, CCR5-tropic HIV-1 infection inpatients 2 years of age and older weighing at least 10 kg in combinationwith other antiretroviral agents, advanced renal cell carcinoma,advanced soft tissue sarcoma who have received prior chemotherapy, manicand mixed episodes associated with Bipolar I, Major Depressive Disorder,irritability associated with Autistic Disorder, Tourette's disorder,agitation associated with schizophrenia or bipolar mania, advanced renalcell carcinoma after failure of one prior systemic therapy, to improveglycemic control in adults with type 2 diabetes mellitus (T2DM) who haveinadequate control with dapagliflozin or who are already treated withdapagliflozin and saxagliptin, progressive, metastatic medullary thyroidcancer (MTC), advanced renal cell carcinoma (RCC) who have receivedprior anti-angiogenic therapy, chronic phase, accelerated phase, orblast phase chronic myeloid leukemia (CML) or Ph+ ALL in adults for whomno other tyrosine kinase inhibitor (TKI) therapy is indicated,T315I-positive CML (chronic phase, accelerated phase, or blast phase) orT315I-positive Philadelphia chromosome in adults, positive acutelymphoblastic leukemia (Ph+ ALL), invasive aspergillosis, invasivemucormycosis, to reduce low-density lipoprotein cholesterol (LDL-C),total cholesterol (TC), apolipoprotein B (apo B), and non-high densitylipoprotein cholesterol (non-HDL-C) in patients with homozygous familialhypercholesterolemia (HoFH), schizophrenia in adults, hormone receptor(HR)-positive, human epidermal growth factor receptor 2 (HER2)-negativeadvanced or metastatic breast cancer in combination with an aromataseinhibitor as initial endocrine based therapy in postmenopausal women, orfulvestrant in women with disease progression following endocrinetherapy, Major Depressive Disorder (MDD), suppression of motor andphonic tics in patients with Tourette's Disorder who have failed torespond satisfactorily to standard treatment, treatment of multiplemyeloma in patients who have received at least two prior therapiesincluding lenalidomide and a proteasome inhibitor and have demonstrateddisease progression on or within 60 days of completion of the lasttherapy, non-small cell lung cancer (NSCLC) whose disease has notprogressed after four cycles of platinum-based first-line chemotherapy,locally advanced or metastatic NSCLC after failure of at least one priorchemotherapy regimen, locally advanced, unresectable or metastaticpancreatic cancer, overactive bladder with symptoms of urge urinaryincontinence, urgency, and urinary frequency, advanced renal cellcarcinoma (RCC) after failure of treatment with sunitinib or sorafenib,subependymal giant cell astrocytoma (SEGA) associated with tuberoussclerosis (TS) who require therapeutic intervention but are notcandidates for curative surgical resection, renal angiomyolipoma,tuberous sclerosis complex, in combination with fulvestrant for thetreatment of women with hormone receptor (HR)-positive, human epidermalgrowth factor receptor 2 (HER2)-negative advanced or metastatic breastcancer with disease progression following endocrine therapy, asmonotherapy for the treatment of adult patients with HRpositive,HER2-negative advanced or metastatic breast cancer with diseaseprogression following endocrine therapy and prior chemotherapy in themetastatic setting, cystic fibrosis (CF) in patients age 2 years andolder who have one mutation in the CFTR gene that is responsive toivacaftor based on clinical and/or in vitro assay data, deleterious orsuspected deleterious germline BRCA-mutated advanced ovarian cancer inadult patients who have been treated with three or more prior lines ofchemotherapy, intermediate or high-risk myelofibrosis, including primarymyelofibrosis, post-polycythemia vera myelofibrosis and post-essentialthrombocythemia myelofibrosis, polycythemia vera patients who have hadan inadequate response to or are intolerant of hydroxyurea, as anadjunctive therapy to antidepressants for the treatment of majordepressive disorder (MDD), schizophrenia, cystic fibrosis (CF) patientsaged 12 years and older who are homozygous for the F508del mutation orwho have at least one mutation in the cystic fibrosis transmembraneconductance regulator (CFTR) gene that is responsive totezacaftor/ivacaftor based on in vitro data and/or clinical evidence,metastatic colorectal cancer (CRC) patients who have been previouslytreated with fluoropyrimidine-, oxaliplatin- and irinotecan-basedchemotherapy, an antiVEGF therapy, and, if RAS wild-type, an anti-EGFRtherapy, locally advanced, unresectable or metastatic gastrointestinalstromal tumor (GIST) patients who have been previously treated withimatinib mesylate and sunitinib malate, hepatocellular carcinoma (HCC)who have been previously treated with sorafenib, use with sofosbuvir,with or without ribavirin, for the treatment of chronic HCV genotype 1or 3 infection, metastatic non-small cell lung cancer (NSCLC) patientswhose tumors are anaplastic lymphoma kinase (ALK) or ROS1-positive asdetected by an FDA-approved test, opioid induced constipation (OIC) inadult patients with chronic non-cancer pain, including patients withchronic pain related to prior cancer or its treatment who do not requirefrequent (e.g., weekly) opioid dosage escalation, unresectable ormetastatic melanoma with BRAF V600E mutation as detected by anFDA-approved test, in combination with trametinib, for the treatment ofpatients with unresectable or metastatic melanoma with BRAF V600E orV600K mutations as detected by an FDA-approved test, adjuvant treatmentof patients with melanoma with BRAF V600E or V600K mutations, asdetected by an FDA-approved test, and involvement of lymph node(s),following complete resection, metastatic non-small cell lung cancer(NSCLC) with BRAF V600E mutation as detected by an FDA-approved test,locally advanced or metastatic anaplastic thyroid cancer (ATC) inpatients with BRAF V600E mutation and with no satisfactory locoregionaltreatment options, with or without ribavirin for treatment of chronicHCV genotypes 1 or 4 infection in adults, the treatment of patients withnon-metastatic castration-resistant prostate cancer, the treatment ofpatients with anaplastic lymphoma kinase (ALK)-positive metastaticnon-small cell lung cancer (NSCLC) who have progressed on or areintolerant to crizotinib, the treatment of seizures associated withLennox-Gastaut syndrome or Dravet syndrome in patients 2 years of ageand older, the treatment of adult patients with relapsed follicularlymphoma (FL) who have received at least two prior systemic therapies,the treatment of adult patients with relapsed or refractory chroniclymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) after atleast two prior therapies, the treatment of adult patients with relapsedor refractory follicular lymphoma (FL) after at least two prior systemictherapies, in combination with binimetinib, for the treatment ofpatients with unresectable or metastatic melanoma with a BRAF V600E orV600K mutation, as detected by an FDA-approved test, the treatment ofpremenopausal women with acquired, generalized hypoactive sexual desiredisorder (HSDD) as characterized by low sexual desire that causes markeddistress or interpersonal difficulty and is not due to a co-existingmedical or psychiatric condition, problems within the relationship, orthe effects of a medication or other drug substance, to reduce the riskof hospitalization for worsening heart failure in patients with stable,symptomatic chronic heart failure with left ventricular ejectionfraction ≤35%, who are in sinus rhythm with resting heart rate ≥70 beatsper minute and either are on maximally tolerated doses of beta-blockersor have a contraindication to beta-blocker use, the treatment of adultpatients with relapsed or refractory acute myeloid leukemia (AML) with asusceptible IDH1 mutation as detected by an FDA-approved test, thetreatment of patients with multiple myeloma who have received at least 2prior regimens, including bortezomib and an immunomodulatory agent, thetreatment of adult patients with locally advanced basal cell carcinoma(BCC) that has recurred following surgery or radiation therapy, or thosewho are not candidates for surgery or radiation therapy, the treatmentof patients with unresectable or metastatic melanoma with BRAF V600Emutation as detected by an FDA-approved test, and the treatment ofpatients with Erdheim-Chester Disease with BRAF V600 mutation.

111. The method of embodiment 110, wherein said CYP3A4 substrate drug isselected from the group consisting of lurasidone, ranolazine,lumacaftor/ivacaftor, venetoclax, trabectedin, ribociclib succinate,deflazacort, cinacalcet hydrochloride, pimavanserin tartrate,aripiprazole lauroxil, cariprazine hydrochloride, simeprevir sodium,everolimus, saxagliptin hydrochloride, saxagliptin/metforminhydrochloride, ticagrelor, vilazodone hydrochloride, apixaban,tofacitinib citrate, eletriptan hydrobromide, nilotinib hydrochloridemonohydrate, dronedarone hydrochloride, fluticasonepropionate/salmeterol xinafoate, rivaroxaban, tadalafil, ibrutinib,cobimetinib, colchicine, cabazitaxel, tolvaptan, fosaprepitantdimeglumine, aprepitant, solifenacin succinate, erlotinib hydrochloride,ado-trastuzumab ematansine, bosutinib monohydrate, sunitinib malate,fesoterodine fumarate, maraviroc, pazopanib hydrochloride, aripiprazole,axitinib, dapagliflozin/saxagliptin, cabozantinib S-malate, ponatinibhydrochloride, isavuconazonium sulfate, lomitapide mesylate,iloperidone, palbociclib, levomilnacipran hydrochloride, pimozide,pomalidomide, abemaciclib, ivacaftor, ruxolitinib phosphate,brexpiprazole, ivacaftor/tezacaftor, regorafenib, daclatasvir,crizotinib, naloxegol oxalate, dabrafenib, olaparib, elbasvir andgrazoprevir, apalutamide, brigatinib, cannabidiol, copanlisib,duvelisib, encorafenib, flibanserin, ivabradine, ivosidenib,panobinostat, sonidegib, and vemurafenib.

112. The method of embodiment 111, wherein the CYP3A4 substrate drug islurasidone.

113. The method of embodiment 111, wherein the CYP3A4 substrate drug isranolazine.

114. The method of embodiment 111, wherein the CYP3A4 substrate drug istadalafil.

115. The method of any of embodiments 110-114, wherein the patient isobese.

116. The method of embodiment 115, wherein the patient has at least oneof the following characteristics:

i) BMI of at least about 35;

ii) % IBW of at least about 150%;

iii) waist size greater than about 42 inches;

iv) % body fat greater than about 40%;

v) total body fat greater than about 40 kg; and

vi) medically diagnosed as obese.

117. The method of any of embodiments 110-116, wherein the CYP3A4substrate drug is ranolazine, and the AUC of ranolazine is maintained ata level of no more than about 150% of a normal baseline AUC ofranolazine.

118. The method of any of embodiments 110-116, wherein the CYP3A4substrate drug is ranolazine, and the C_(max) of ranolazine ismaintained at a level of no more than about 150% of a normal baselineC_(max) of ranolazine.

119. The method of any of embodiments 110-116, wherein the CYP3A4substrate drug is lurasidone, and the AUC of lurasidone is maintained ata level of no more than about 216% of a normal baseline AUC oflurasidone.

120. The method of any of embodiments 110-116, wherein the CYP3A4substrate drug is lurasidone, and the C_(max) of lurasidone ismaintained at a level of no more than about 210% of a normal baselineC_(max) of lurasidone.

121. The method of any of embodiments 110-116, wherein the CYP3A4substrate drug is tadalafil, and the AUC of tadalafil is maintained at alevel of no more than about 410% of a normal baseline AUC of tadalafil.

122. The method of any of embodiments 110-116, wherein the CYP3A4substrate drug is tadalafil, and the a Cmax of tadalafil is maintainedat a level of no more than about 120% of a normal baseline Cmax oftadalafil.

123. The method of embodiments 110-122, wherein the patient is a poor orintermediate CYP3A4 metabolizer.

124. A method of treating a patient with a CYP3A4 substrate drug whichis contraindicated for concomitant use with a strong CYP3A4 inhibitor,comprising:

(a) delaying a first treatment, or prescribing a delay in the firsttreatment, of the CYP3A4 substrate drug for at least about 2-21 daysafter stopping administration of the posaconazole regimen; and then

(d) treating the patient with the CYP3A4 substrate drug at a dose whichis less than or equal to about 50% of the reference dose for at leastabout 2-21 days after stopping administration of the posaconazoleregimen;

wherein the disease or condition treated with the CYP3A4 substrate drugis selected from the group consisting of schizophrenia in adults andadolescents (13 to 17 years), depressive episodes associated withBipolar I Disorder (bipolar depression) in adults and pediatrics (10 to17 years) as monotherapy or as adjunctive therapy with lithium orvalproate, moderate bipolar depression, severe bipolar depression,severe bipolar depression with acute suicidal ideation and behavior(ASIB), chronic angina, cystic fibrosis in patients 6 years and olderwho are homozygous for the F508del mutation in the CFTR gene, chroniclymphocytic leukemia in patients with 17p deletion, who have received atleast one prior therapy, unresectable or metastatic liposarcoma orleiomyosarcoma in patients who received a prior anthracycline-containingregimen, advanced or metastatic breast cancer in postmenopausal womenwith hormone receptor (HR)-positive, human epidermal growth factorreceptor 2 (HER2)-negative advanced or metastatic breast cancer,negative advanced or metastatic breast cancer in combination with anaromatase inhibitor for postmenopausal women, Duchenne musculardystrophy (DMD), secondary hyperparathyroidism (HPT) in patients withchronic kidney disease (CKD) on dialysis, hypercalcemia in patients withparathyroid carcinoma or in patients with primary HPT for whoparathyroidectomy would be indicated on the basis of serum calciumlevels, but who are unable to undergo parathyroidectomy, hallucinationsand delusions associated with Parkinson's disease psychosis,schizophrenia, acute manic or mixed episodes associated with bipolar Idisorder, chronic hepatitis C (CHC) infection as a component of acombination antiviral treatment regimen with peginterferon alfa andribavirin in HCV genotype 1 infected subjects with compensated liverdisease, postmenopausal women with advanced hormone receptor-positive,HER2-negative breast cancer (advanced HR+BC), e.g., in combination withexemestane after failure of treatment with letrozole or anastrozole,progressive neuroendocrine tumors of pancreatic origin (PNET),progressive, well-differentiated, non-functional neuroendocrine tumors(NET) of gastrointestinal (GI) or lung origin that are unresectable,locally advanced or metastatic, advanced renal cell carcinoma (RCC),e.g., after failure of treatment with sunitinib or sorafenib, renalangiomyolipoma and tuberous sclerosis complex (TSC), not requiringimmediate surgery, TSC in patients who have subependymal giant cellastrocytoma (SEGA) that require therapeutic intervention but are notcandidates for surgical resection, type 2 diabetes mellitus in adults asan adjunct to diet and exercise to improve glycemic control, majordepressive disorder (MDD), thrombotic cardiovascular events (e.g.,cardiovascular death, myocardial infarction, or stroke) in patients withacute coronary syndrome (ACS), stroke and systemic embolism in patientswith nonvalvular atrial fibrillation, deep vein thrombosis (DVT), whichmay lead to pulmonary embolism (PE) in patients who have undergone hipor knee replacement surgery, DVT, PE, recurrent DVT and PE followinginitial therapy, moderate to severe active rheumatoid arthritis inpatients who have had inadequate response or tolerance to methotrexate,acute migraine with or without aura, chronic phase and accelerated phasePhiladelphia chromosome positive chronic myeloid leukemia (Ph+ CML) innewly diagnosed patients or in patients resistant to or intolerant toprior therapy that included imatinib, atrial fibrillation (AF) inpatients with a history of paroxysmal or persistant AF or atrial flutter(AFK), who are in sinus rhythm or will be cardioverted, asthma inpatients aged 4 years and older, airflow obstruction and reducingexacerbations in patients with chronic obstructive pulmonary disease,erectile dysfunction (ED), benign prostatic hyperplasia (BPH), pulmonaryarterial hypertension (PAH) (WHO Group 1) to improve exercise ability,gout flares, Familial Mediterranean fever, antiretroviral therapy,anxiety disorders, panic disorders, seizures, insomnia, hypertension,cardiovascular disease, hyperlipidemia, cancer, such as primary kidneycancer, advanced primary liver cancer, radioactive iodine resistantadvanced thyroid carcinoma, renal cell carcinoma, imatinib-resistantgastrointestinal stromal tumor, mantle cell lymphoma in patients whohave received at least one prior therapy, chronic lymphocyticleukemia/small lymphocytic lymphoma, chronic lymphocytic leukemia/smalllymphocytic lymphoma with 17p deletion, Waldenström's macroglobulinemia,marginal zone lymphoma who require systemic therapy and have received atleast one prior anti-CD20-based therapy, unresectable or metastaticmelanoma with a BRAF V600E or V600K mutation, allergies,transplantation, hormone-refractory metastatic prostate cancerpreviously treated with a docetaxel-containing treatment regimen,hormone-refractory metastatic prostate cancer previously treated with adocetaxel-containing treatment regimen, treatment of clinicallysignificant hypervolemic and euvolemic hyponatremia, including patientswith heart failure and Syndrome of Inappropriate Antidiuretic Hormone(SIADH), prevention of acute and delayed nausea and vomiting associatedwith initial and repeat courses of highly emetogenic cancer chemotherapy(HEC) including high-dose cisplatin, prevention of delayed nausea andvomiting associated with initial and repeat courses of moderatelyemetogenic cancer chemotherapy (MEC), over-active bladder with symptomsof urge urinary incontinence, urgency, and urinary frequency, metastaticnon-small cell lung cancer (NSCLC) whose tumors have epidermal growthfactor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitutionmutations as detected by an FDA-approved test receiving first-line,maintenance, or second or greater line treatment after progression,locally advanced, unresectable or metastatic pancreatic cancer, incombination with gemcitabine, HER2-positive, metastatic breast cancerwho previously received trastuzumab and a taxane, separately or incombination in patients who have either: received prior therapy formetastatic disease or developed disease recurrence during or within sixmonths of completing adjuvant therapy, chronic, accelerated, or blastphase Ph+ chronic myelogenous leukemia (CML) in adults with resistanceor intolerance to prior therapy, gastrointestinal stromal tumor (GIST)after disease progression on or intolerance to imatinib mesylate,advanced renal cell carcinoma (RCC), progressive, well-differentiatedpancreatic neuroendocrine tumors (pNET) in patients with unresectablelocally advanced or metastatic disease, CCR5-tropic HIV-1 infection inpatients 2 years of age and older weighing at least 10 kg in combinationwith other antiretroviral agents, advanced renal cell carcinoma,advanced soft tissue sarcoma who have received prior chemotherapy, manicand mixed episodes associated with Bipolar I, Major Depressive Disorder,irritability associated with Autistic Disorder, Tourette's disorder,agitation associated with schizophrenia or bipolar mania, advanced renalcell carcinoma after failure of one prior systemic therapy, to improveglycemic control in adults with type 2 diabetes mellitus (T2DM) who haveinadequate control with dapagliflozin or who are already treated withdapagliflozin and saxagliptin, progressive, metastatic medullary thyroidcancer (MTC), advanced renal cell carcinoma (RCC) who have receivedprior anti-angiogenic therapy, chronic phase, accelerated phase, orblast phase chronic myeloid leukemia (CML) or Ph+ ALL in adults for whomno other tyrosine kinase inhibitor (TKI) therapy is indicated,T315I-positive CML (chronic phase, accelerated phase, or blast phase) orT315I-positive Philadelphia chromosome in adults, positive acutelymphoblastic leukemia (Ph+ ALL), invasive aspergillosis, invasivemucormycosis, to reduce low-density lipoprotein cholesterol (LDL-C),total cholesterol (TC), apolipoprotein B (apo B), and non-high densitylipoprotein cholesterol (non-HDL-C) in patients with homozygous familialhypercholesterolemia (HoFH), schizophrenia in adults, hormone receptor(HR)-positive, human epidermal growth factor receptor 2 (HER2)-negativeadvanced or metastatic breast cancer in combination with an aromataseinhibitor as initial endocrine based therapy in postmenopausal women, orfulvestrant in women with disease progression following endocrinetherapy, Major Depressive Disorder (MDD), suppression of motor andphonic tics in patients with Tourette's Disorder who have failed torespond satisfactorily to standard treatment, treatment of multiplemyeloma in patients who have received at least two prior therapiesincluding lenalidomide and a proteasome inhibitor and have demonstrateddisease progression on or within 60 days of completion of the lasttherapy, non-small cell lung cancer (NSCLC) whose disease has notprogressed after four cycles of platinum-based first-line chemotherapy,locally advanced or metastatic NSCLC after failure of at least one priorchemotherapy regimen, locally advanced, unresectable or metastaticpancreatic cancer, overactive bladder with symptoms of urge urinaryincontinence, urgency, and urinary frequency, advanced renal cellcarcinoma (RCC) after failure of treatment with sunitinib or sorafenib,subependymal giant cell astrocytoma (SEGA) associated with tuberoussclerosis (TS) who require therapeutic intervention but are notcandidates for curative surgical resection, renal angiomyolipoma,tuberous sclerosis complex, in combination with fulvestrant for thetreatment of women with hormone receptor (HR)-positive, human epidermalgrowth factor receptor 2 (HER2)-negative advanced or metastatic breastcancer with disease progression following endocrine therapy, asmonotherapy for the treatment of adult patients with HRpositive,HER2-negative advanced or metastatic breast cancer with diseaseprogression following endocrine therapy and prior chemotherapy in themetastatic setting, cystic fibrosis (CF) in patients age 2 years andolder who have one mutation in the CFTR gene that is responsive toivacaftor based on clinical and/or in vitro assay data, deleterious orsuspected deleterious germline BRCA-mutated advanced ovarian cancer inadult patients who have been treated with three or more prior lines ofchemotherapy, intermediate or high-risk myelofibrosis, including primarymyelofibrosis, post-polycythemia vera myelofibrosis and post-essentialthrombocythemia myelofibrosis, polycythemia vera patients who have hadan inadequate response to or are intolerant of hydroxyurea, as anadjunctive therapy to antidepressants for the treatment of majordepressive disorder (MDD), schizophrenia, cystic fibrosis (CF) patientsaged 12 years and older who are homozygous for the F508del mutation orwho have at least one mutation in the cystic fibrosis transmembraneconductance regulator (CFTR) gene that is responsive totezacaftor/ivacaftor based on in vitro data and/or clinical evidence,metastatic colorectal cancer (CRC) patients who have been previouslytreated with fluoropyrimidine-, oxaliplatin- and irinotecan-basedchemotherapy, an antiVEGF therapy, and, if RAS wild-type, an anti-EGFRtherapy, locally advanced, unresectable or metastatic gastrointestinalstromal tumor (GIST) patients who have been previously treated withimatinib mesylate and sunitinib malate, hepatocellular carcinoma (HCC)who have been previously treated with sorafenib, use with sofosbuvir,with or without ribavirin, for the treatment of chronic HCV genotype 1or 3 infection, metastatic non-small cell lung cancer (NSCLC) patientswhose tumors are anaplastic lymphoma kinase (ALK) or ROS1-positive asdetected by an FDA-approved test, opioid induced constipation (OIC) inadult patients with chronic non-cancer pain, including patients withchronic pain related to prior cancer or its treatment who do not requirefrequent (e.g., weekly) opioid dosage escalation, unresectable ormetastatic melanoma with BRAF V600E mutation as detected by anFDA-approved test, in combination with trametinib, for the treatment ofpatients with unresectable or metastatic melanoma with BRAF V600E orV600K mutations as detected by an FDA-approved test, adjuvant treatmentof patients with melanoma with BRAF V600E or V600K mutations, asdetected by an FDA-approved test, and involvement of lymph node(s),following complete resection, metastatic non-small cell lung cancer(NSCLC) with BRAF V600E mutation as detected by an FDA-approved test,locally advanced or metastatic anaplastic thyroid cancer (ATC) inpatients with BRAF V600E mutation and with no satisfactory locoregionaltreatment options, with or without ribavirin for treatment of chronicHCV genotypes 1 or 4 infection in adults, the treatment of patients withnon-metastatic castration-resistant prostate cancer, the treatment ofpatients with anaplastic lymphoma kinase (ALK)-positive metastaticnon-small cell lung cancer (NSCLC) who have progressed on or areintolerant to crizotinib, the treatment of seizures associated withLennox-Gastaut syndrome or Dravet syndrome in patients 2 years of ageand older, the treatment of adult patients with relapsed follicularlymphoma (FL) who have received at least two prior systemic therapies,the treatment of adult patients with relapsed or refractory chroniclymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) after atleast two prior therapies, the treatment of adult patients with relapsedor refractory follicular lymphoma (FL) after at least two prior systemictherapies, in combination with binimetinib, for the treatment ofpatients with unresectable or metastatic melanoma with a BRAF V600E orV600K mutation, as detected by an FDA-approved test, the treatment ofpremenopausal women with acquired, generalized hypoactive sexual desiredisorder (HSDD) as characterized by low sexual desire that causes markeddistress or interpersonal difficulty and is not due to a co-existingmedical or psychiatric condition, problems within the relationship, orthe effects of a medication or other drug substance, to reduce the riskof hospitalization for worsening heart failure in patients with stable,symptomatic chronic heart failure with left ventricular ejectionfraction ≤35%, who are in sinus rhythm with resting heart rate ≥70 beatsper minute and either are on maximally tolerated doses of beta-blockersor have a contraindication to beta-blocker use, the treatment of adultpatients with relapsed or refractory acute myeloid leukemia (AML) with asusceptible IDH1 mutation as detected by an FDA-approved test, thetreatment of patients with multiple myeloma who have received at least 2prior regimens, including bortezomib and an immunomodulatory agent, thetreatment of adult patients with locally advanced basal cell carcinoma(BCC) that has recurred following surgery or radiation therapy, or thosewho are not candidates for surgery or radiation therapy, the treatmentof patients with unresectable or metastatic melanoma with BRAF V600Emutation as detected by an FDA-approved test, and the treatment ofpatients with Erdheim-Chester Disease with BRAF V600 mutation.

125. The method of embodiment 124, wherein said CYP3A4 substrate drug isselected from the group consisting of lurasidone, ranolazine,lumacaftor/ivacaftor, venetoclax, trabectedin, ribociclib succinate,deflazacort, cinacalcet hydrochloride, pimavanserin tartrate,aripiprazole lauroxil, cariprazine hydrochloride, simeprevir sodium,everolimus, saxagliptin hydrochloride, saxagliptin/metforminhydrochloride, ticagrelor, vilazodone hydrochloride, apixaban,tofacitinib citrate, eletriptan hydrobromide, nilotinib hydrochloridemonohydrate, dronedarone hydrochloride, fluticasonepropionate/salmeterol xinafoate, rivaroxaban, tadalafil, ibrutinib,cobimetinib, colchicine, cabazitaxel, tolvaptan, fosaprepitantdimeglumine, aprepitant, solifenacin succinate, erlotinib hydrochloride,ado-trastuzumab ematansine, bosutinib monohydrate, sunitinib malate,fesoterodine fumarate, maraviroc, pazopanib hydrochloride, aripiprazole,axitinib, dapagliflozin/saxagliptin, cabozantinib S-malate, ponatinibhydrochloride, isavuconazonium sulfate, lomitapide mesylate,iloperidone, palbociclib, levomilnacipran hydrochloride, pimozide,pomalidomide, abemaciclib, ivacaftor, ruxolitinib phosphate,brexpiprazole, ivacaftor/tezacaftor, regorafenib, daclatasvir,crizotinib, naloxegol oxalate, dabrafenib, olaparib, elbasvir andgrazoprevir, apalutamide, brigatinib, cannabidiol, copanlisib,duvelisib, encorafenib, flibanserin, ivabradine, ivosidenib,panobinostat, sonidegib, and vemurafenib.

126. The method of embodiment 125, wherein the CYP3A4 substrate drug islurasidone.

127. The method of embodiment 125, wherein the CYP3A4 substrate drug isranolazine.

128. The method of embodiment 125, wherein the CYP3A4 substrate drug istadalafil.

129. The method of any of embodiments 124-128, wherein the patient isobese.

130. The method of embodiment 129, wherein the patient has at least oneof the following characteristics:

i) BMI of at least about 35;

ii) % IBW of at least about 150%;

iii) waist size greater than about 42 inches;

iv) % body fat greater than about 40%;

v) total body fat greater than about 40 kg; and

vi) medically diagnosed as obese.

131. The method of any of embodiments 124-132, wherein the CYP3A4substrate drug is ranolazine, and the AUC of ranolazine is maintained ata level of no more than about a normal baseline AUC of ranolazine toabout 150% of the normal baseline AUC of ranolazine.

132. The method of any of embodiments 124-132, wherein the CYP3A4substrate drug is ranolazine, and the C_(max) of ranolazine ismaintained at a level of no more than about a normal baseline C_(max) ofranolazine to about 150% of the normal baseline C_(max) of ranolazine.

133. The method of any of embodiments 124-132, wherein the CYP3A4substrate drug is lurasidone, and the AUC of lurasidone is maintained ata level of no more than about a normal baseline AUC of lurasidone toabout 216% of the normal baseline AUC of lurasidone.

134. The method of any of embodiments 124-132, wherein the CYP3A4substrate drug is lurasidone, and the C_(max) of lurasidone ismaintained at a level of no more than about a normal baseline C_(max) oflurasidone to about 210% of the normal baseline C_(max) of lurasidone.

135. The method of any of embodiments 124-132, wherein the CYP3A4substrate drug is tadalafil, and the AUC of tadalafil is maintained at alevel of no more than about 410% of a normal baseline AUC of tadalafil.

136. The method of any of embodiments 124-132, wherein the CYP3A4substrate drug is tadalafil, and the a Cmax of tadalafil is maintainedat a level of no more than about 120% of a normal baseline Cmax oftadalafil.

137. The method of any one of embodiments 134-136, wherein the patientis a poor or intermediate CYP3A4 metabolizer.

138. The method of any of embodiments 2, 16, 31, 45, 60, 82, 96, 111, or125, wherein the wherein the CYP3A4 substrate drug is erlotinib.

139. The method of any of embodiments 2, 16, 31, 45, 60, 82, 96, 111, or125, wherein the wherein the CYP3A4 substrate drug is solifenacinsuccinate.

140. The method of any of embodiments 2, 16, 31, 45, 60, 82, 96, 111, or125, wherein the wherein the CYP3A4 substrate drug is everolimus.

141, The method of any of embodiments 2, 16, 31, 45, 60, 82, 96, 111, or125, wherein the wherein the CYP3A4 substrate drug is abemaciclib.

142. The method of any of embodiments 2, 16, 31, 45, 60, 82, 96, 111, or125, wherein the wherein the CYP3A4 substrate drug is ivacaftor.

143. The method of any of embodiments 2, 16, 31, 45, 60, 82, 96, 111, or125, wherein the wherein the CYP3A4 substrate drug is ruxolitinibphosphate.

144. The method of any of embodiments 2, 16, 31, 45, 60, 82, 96, 111, or125, wherein the wherein the CYP3A4 substrate drug is brexpiprazole.

145. The method of any of embodiments 2, 16, 31, 45, 60, 82, 96, 111, or125, wherein the wherein the CYP3A4 substrate drug isivacaftor/tezacaftor.

146. The method of any of embodiments 2, 16, 31, 45, 60, 82, 96, 111, or125, wherein the wherein the CYP3A4 substrate drug is regorafenib.

147. The method of any of embodiments 2, 16, 31, 45, 60, 82, 96, 111, or125, wherein the wherein the CYP3A4 substrate drug is daclatasvir.

148. The method of any of embodiments 2, 16, 31, 45, 60, 82, 96, 111, or125, wherein the wherein the CYP3A4 substrate drug is crizotinib.

149. The method of any of embodiments 2, 16, 31, 45, 60, 82, 96, 111, or125, wherein the wherein the CYP3A4 substrate drug is naloxegol oxalate.

150. The method of any of embodiments 2, 16, 31, 45, 60, 82, 96, 111, or125, wherein the wherein the CYP3A4 substrate drug is dabrafenib.

151. The method of any of embodiments 2, 16, 31, 45, 60, 82, 96, 111, or125, wherein the wherein the CYP3A4 substrate drug is elbasvir andgrazoprevir.

152. The method of any of embodiments 1, 2, 6, 7, 14-16, 20, 21, 28-31,35, 36, 43-45, 49, 50, 57-60, 64, 65, 80-82, 86, 87, 94-96, 100, 101,108-111, 115, 116, 123-125, 129, 130, or 137-140, wherein the CYP3A4substrate drug is erlotinib, and the AUC of erlotinib is maintained at alevel of no more than about 164% of the normal baseline AUC oferlotinib.

153. The method of any of embodiments 1, 2, 6, 7, 14-16, 20, 21, 28-31,35, 36, 43-45, 49, 50, 57-60, 64, 65, 80-82, 86, 87, 94-96, 100, 101,108-111, 115, 116, 123-125, 129, 130, or 137-140, wherein the CYP3A4substrate drug is erlotinib, and the Cmax of erlotinib is maintained ata level of no more than about 167% of the normal baseline Cmax oferlotinib.

154. The method of any of embodiments 1, 2, 6, 7, 14-16, 20, 21, 28-31,35, 36, 43-45, 49, 50, 57-60, 64, 65, 80-82, 86, 87, 94-96, 100, 101,108-111, 115, 116, 123-125, 129, 130, or 137-140, wherein the CYP3A4substrate drug is solifenacin succinate, and the AUC of solifenacinsuccinate is maintained at a level of no more than about 270% of thenormal baseline AUC of solifenacin succinate.

155. The method of any of embodiments 1, 2, 6, 7, 14-16, 20, 21, 28-31,35, 36, 43-45, 49, 50, 57-60, 64, 65, 80-82, 86, 87, 94-96, 100, 101,108-111, 115, 116, 123-125, 129, 130, or 137-140, wherein the CYP3A4substrate drug is solifenacin succinate, and the C_(max) of solifenacinsuccinate is maintained at a level of no more than about 150% of thenormal baseline C_(max) of solifenacin succinate.

156. The method of any of embodiments 1, 2, 6, 7, 14-16, 20, 21, 28-31,35, 36, 43-45, 49, 50, 57-60, 64, 65, 80-82, 86, 87, 94-96, 100, 101,108-111, 115, 116, 123-125, 129, 130, or 137-140, wherein the CYP3A4substrate drug is everolimus, and the AUC of everolimus is maintained ata level of no more than about 440% of a normal baseline AUC ofeverolimus.

157. The method of any of embodiments 1, 2, 6, 7, 14-16, 20, 21, 28-31,35, 36, 43-45, 49, 50, 57-60, 64, 65, 80-82, 86, 87, 94-96, 100, 101,108-111, 115, 116, 123-125, 129, 130, or 137-140, wherein the CYP3A4substrate drug is everolimus, and the a Cmax of everolimus is maintainedat a level of no more than about 200% of a normal baseline Cmax ofeverolimus.

Embodiments II

1A. A method of treating a patient in need thereof with a CYP3A4substrate drug, wherein the patient is treated with posaconazole,comprising:

(a) selecting a reference dose of the CYP3A4 substrate drug based on thepatient's age and/or condition;

(b) stopping posaconazole treatment;

(c) waiting at least two days after stopping posaconazole treatment; andthen

(d) administering the CYP3A4 substrate drug as soon as it is safe to doso.

1B. The method of embodiment 1A, wherein the CYP3A4 substrate drug isadministered in step (d) as soon as at least one of the patient's AUC,Cmax, AUC GMR, or Cmax GMR reaches a target safe level disclosed herein,e.g., as provided in Table A for the CYP3A4 substrate drug.

2A. A method of treating a patient in need thereof with a CYP3A4substrate drug, wherein the patient is treated with posaconazole,comprising:

(a) selecting a reference dose of the CYP3A4 substrate drug based on thepatient's age and/or condition;

(b) stopping posaconazole treatment;

(c) waiting at least two days after stopping posaconazole treatment; andthen

(d) administering the CYP3A4 substrate drug to achieve an AUC of theCYP3A4 substrate that is at least about 105% of a predicted AUC for theday on which that CYP3A4 substrate drug is administered.

2B. The method of embodiment 2A, wherein the AUC of the CYP3A4 substratedrug in step (d) ranges from 105% to a target safe level disclosedherein, e.g., as provided in Table A for the CYP3A4 substrate drug.

3A. A method of treating a patient in need thereof with a CYP3A4substrate drug, wherein the patient is treated with posaconazole,comprising:

(a) selecting a reference dose of the CYP3A4 substrate drug based on thepatient's age and/or condition;

(b) stopping posaconazole treatment;

(c) waiting at least two days after stopping posaconazole treatment; andthen

(d) administering the CYP3A4 substrate drug to achieve a GMR AUC of theCYP3A4 substrate which is at least about 1.05 fold of the expected AUC.

3B. The method of embodiment 3A, wherein the AUC of the CYP3A4 substratedrug in step (d) ranges from about 1.05 fold to a target safe leveldisclosed herein, e.g., as provided in Table A for the CYP3A4 substratedrug.

4A. A method of treating a patient in need thereof with a CYP3A4substrate drug, wherein the patient is treated with posaconazole,comprising:

(a) selecting a reference dose of the CYP3A4 substrate drug based on thepatient's age and/or condition;

(b) stopping posaconazole treatment;

(c) waiting at least two days after stopping posaconazole treatment; andthen

(d) administering the CYP3A4 substrate drug to achieve an AUC of theCYP3A4 substrate that does not exceed a maximum level where benefits oftreating the patient outweigh risks of elevated exposure to the CYP3A4substrate drug.

4B. The method of embodiment 4A, wherein the AUC of the CYP3A4 substratedrug in step (d) does not exceed a target safe level disclosed herein,e.g., as provided in Table A for the CYP3A4 substrate drug.

5A. A method of treating a patient in need thereof with a CYP3A4substrate drug, wherein the patient is treated with posaconazole,comprising:

(a) selecting a reference dose of the CYP3A4 substrate drug based on thepatient's age and/or condition;

(b) stopping posaconazole treatment;

(c) waiting at least two days after stopping posaconazole treatment; andthen

(d) administering the CYP3A4 substrate drug to achieve a GMR AUC of theCYP3A4 substrate that does not exceed a maximum level where benefits oftreating the patient outweigh risks of elevated exposure to the CYP3A4substrate drug.

5B. The method of embodiment 5A, wherein the AUC of the CYP3A4 substratedrug in step (d) does not exceed a target safe level disclosed herein,e.g., as provided in Table A for the CYP3A4 substrate drug.

6A. A method of treating a patient in need thereof with a CYP3A4substrate drug, wherein the patient is treated with posaconazole,comprising:

(a) selecting a reference dose of the CYP3A4 substrate drug based on thepatient's age and/or condition;

(b) stopping posaconazole treatment

(c) waiting at least two days after stopping posaconazole treatment; andthen and then

(d) administering the CYP3A4 substrate drug to achieve at least one of aGMR AUC or GMR Cmax of the CYP3A4 substrate which is:

-   -   (i) at least about 1.05 fold greater than the predicted AUC or        Cmax; and    -   (ii) does not exceed maximum level where benefits of treating        the patient outweigh risks of elevated exposure to the CYP3A4        substrate drug.

6B. The method of embodiment 6A, wherein the GMR AUC or GMR Cmax of theCYP3A4 substrate drug in step (d)(ii) does not exceed a target safelevel disclosed herein, e.g., as listed in Table A for the CYP3A4substrate drug.

7A. A method of treating a patient in need thereof with a CYP3A4substrate drug, wherein the patient is treated with posaconazole,comprising:

(a) selecting a reference dose of the CYP3A4 substrate drug based on thepatient's age and/or condition;

(b) stopping posaconazole treatment

(c) waiting at least two days after stopping posaconazole treatment; andthen

(d) administering the CYP3A4 substrate drug:

-   -   (i) as soon as steady state posaconazole levels (Css ng/mL) are        reduced by at least about 50%; and    -   (ii) the at least one of the AUC, Cmax, GMR AUC, or GMR Cmax are        at or below a target safe level (e.g., as disclosed in Table A)        but above the expected level.

8. The method of any one of embodiments 1A-1B, 2A-2B, 3A-3B, 4A-4B,5A-5B, 6A-6B, or 7 wherein the CYP3A4 substrate drug is selected fromthe group consisting of lurasidone, ranolazine, lumacaftor/ivacaftor,venetoclax, trabectedin, ribociclib succinate, deflazacort, cinacalcethydrochloride, pimavanserin tartrate, aripiprazole lauroxil, cariprazinehydrochloride, simeprevir sodium, everolimus, saxagliptin hydrochloride,saxagliptin/metformin hydrochloride, ticagrelor, vilazodonehydrochloride, apixaban, tofacitinib citrate, eletriptan hydrobromide,nilotinib hydrochloride monohydrate, dronedarone hydrochloride,fluticasone propionate/salmeterol xinafoate, rivaroxaban, tadalafil,ibrutinib, cobimetinib, colchicine, cabazitaxel, tolvaptan,fosaprepitant dimeglumine, aprepitant, solifenacin succinate, erlotinibhydrochloride, ado-trastuzumab ematansine, bosutinib monohydrate,sunitinib malate, fesoterodine fumarate, maraviroc, pazopanibhydrochloride, aripiprazole, axitinib, dapagliflozin/saxagliptin,cabozantinib S-malate, ponatinib hydrochloride, isavucazonium sulfate,lomitapide mesylate, iloperidone, palbociclib, levomilacipranhydrochloride, pimozide, pomalidomide, abemaciclib, ivacaftor, olaparib,ruxolitinib phosphate, brexpiprazole, ivacaftor/tezacaftor, regorafenib,daclatasvir, crizotinib, naloxegol oxalate, dabrafenib,elbasvir/grazoprevir, apalutamide, brigatinib, cannabidiol, copanlisib,duvelisib, encorafenib, flibanserin, ivabradine, ivosidenib,panobinostat, sonidegib, and vemurafenib.

9. The method of any one of embodiments 1A-1B, 2A-2B, 3A-3B, 4A-4B,5A-5B, 6A-6B, 7 or 8 wherein the CYP3A4 substrate drug is selected fromthe group consisting of cabazitaxel, tolvaptan, fosaprepitantdimeglumine, aprepitant, solifenacin succinate, erlotinib hydrochloride,ado-trastuzumab ematansine, bosutinib monohydrate, sunitinib malate,fesoterodine fumarate, maraviroc, pazopanib hydrochloride, aripiprazole,axitinib, dapagliflozin/saxagliptin, cabozantinib S-malate, ponatinibhydrochloride, isavucazonium sulfate, lomitapide mesylate, iloperidone,palbociclib, levomilacipran hydrochloride, pimozide, pomalidomide,abemaciclib, ivacaftor, olaparib, ruxolitinib phosphate, brexpiprazole,ivacaftor/tezacaftor, regorafenib, daclatasvir, crizotinib, naloxegoloxalate, dabrafenib, elbasvir/grazoprevir, apalutamide, brigatinib,cannabidiol, copanlisib, duvelisib, encorafenib, flibanserin,ivabradine, ivosidenib, panobinostat, sonidegib, and vemurafenib.

10. The method of any one of embodiments 1A-1B, 2A-2B, 3A-3B, 4A-4B,5A-5B, 6A-6B, 7, 8, or 9 wherein the CYP3A4 substrate drug is selectedfrom the group consisting of cabazitaxel, tolvaptan, fosaprepitantdimeglumine, aprepitant, solifenacin succinate, erlotinib hydrochloride,ado-trastuzumab ematansine, bosutinib monohydrate, sunitinib malate,fesoterodine fumarate, maraviroc, pazopanib hydrochloride, aripiprazole,axitinib, dapagliflozin/saxagliptin, cabozantinib S-malate, ponatinibhydrochloride, isavucazonium sulfate, lomitapide mesylate, iloperidone,palbociclib, levomilacipran hydrochloride, pimozide, and pomalidomide.

11. The method of any one of embodiments 1A-1B, 2A-2B, 3A-3B, 4A-4B,5A-5B, 6A-6B, 7, 8, 9, or 10 wherein the CYP3A4 substrate drug isselected from the group consisting of abemaciclib, ivacaftor, olaparib,ruxolitinib phosphate, brexpiprazole, ivacaftor/tezacaftor, regorafenib,daclatasvir, crizotinib, naloxegol oxalate, dabrafenib, andelbasvir/grazoprevir.

12. The method of any one of embodiments 1A-1B, 2A-2B, 3A-3B, 4A-4B,5A-5B, 6A-6B, 7, 8, 9, 10, or 11 wherein the CYP3A4 substrate drug isselected from the group consisting of apalutamide, brigatinib,cannabidiol, copanlisib, duvelisib, encorafenib, flibanserin,ivabradine, ivosidenib, panobinostat, sonidegib, and vemurafenib.

13. The method of any of embodiments 1A-1B, 2A-2B, 3A-3B, 4A-4B, 5A-5B,6A-6B, 7, or 8 wherein the patient is treated for disease or conditionselected from the group consisting of schizophrenia in adults andadolescents (13 to 17 years), depressive episodes associated withBipolar I Disorder (bipolar depression) in adults and pediatric patients(10-17 years) as monotherapy or adjunctive therapy with lithium orvalproate, moderate bipolar depression, severe bipolar depression, andsevere bipolar depression with acute suicidal idealation and behavior(ASIB), chronic angina, cystic fibrosis in patients 6 years and olderwho are homozygous for the F508del mutation in the CFTR gene, chroniclymphocytic leukemia in patients with 17p deletion, who have received atleast one prior therapy, unresectable or metastatic liposarcoma orleiomyosarcoma in patients who received a prior anthracycline-containingregimen, advanced or metastatic breast cancer in postmenopausal womenwith hormone receptor (HR)-positive, human epidermal growth factorreceptor 2 (HER2)-negative advanced or metastatic breast cancer,negative advanced or metastatic breast cancer in combination with anaromatase inhibitor for postmenopausal women, Duchenne musculardystrophy (DMD), secondary hyperparathyroidism (HPT) in patients withchronic kidney disease (CKD) on dialysis, hypercalcemia in patients withparathyroid carcinoma or in patients with primary HPT for whoparathyroidectomy would be indicated on the basis of serum calciumlevels, but who are unable to undergo parathyroidectomy, hallucinationsand delusions associated with Parkinson's disease psychosis,schizophrenia, acute manic or mixed episodes associated with bipolar Idisorder, chronic hepatitis C (CHC) infection as a component of acombination antiviral treatment regimen with peginterferon alfa andribavirin in HCV genotype 1 infected subjects with compensated liverdisease, postmenopausal women with advanced hormone receptor-positive,HER2-negative breast cancer (advanced HR+BC), e.g., in combination withexemestane after failure of treatment with letrozole or anastrozole,progressive neuroendocrine tumors of pancreatic origin (PNET),progressive, well-differentiated, non-functional neuroendocrine tumors(NET) of gastrointestinal (GI) or lung origin that are unresectable,locally advanced or metastatic, advanced renal cell carcinoma (RCC),e.g., after failure of treatment with sunitinib or sorafenib, renalangiomyolipoma and tuberous sclerosis complex (TSC), not requiringimmediate surgery, TSC in patients who have subependymal giant cellastrocytoma (SEGA) that require therapeutic intervention but are notcandidates for surgical resection, type 2 diabetes mellitus in adults asan adjunct to diet and exercise to improve glycemic control, majordepressive disorder (MDD), thrombotic cardiovascular events (e.g.,cardiovascular death, myocardial infarction, or stroke) in patients withacute coronary syndrome (ACS), stroke and systemic embolism in patientswith nonvalvular atrial fibrillation, deep vein thrombosis (DVT), whichmay lead to pulmonary embolism (PE) in patients who have undergone hipor knee replacement surgery, DVT, PE, recurrent DVT and PE followinginitial therapy, moderate to severe active rheumatoid arthritis inpatients who have had inadequate response or tolerance to methotrexate,acute migraine with or without aura, chronic phase and accelerated phasePhiladelphia chromosome positive chronic myeloid leukemia (Ph+ CML) innewly diagnosed patients or in patients resistant to or intolerant toprior therapy that included imatinib, atrial fibrillation (AF) inpatients with a history of paroxysmal or persistant AF or atrial flutter(AFK), who are in sinus rhythm or will be cardioverted, asthma inpatients aged 4 years and older, airflow obstruction and reducingexacerbations in patients with chronic obstructive pulmonary disease,erectile dysfunction (ED), benign prostatic hyperplasia (BPH), pulmonaryarterial hypertension (PAH) (WHO Group 1) to improve exercise ability,gout flares, Familial Mediterranean fever, antiretroviral therapy,anxiety disorders, panic disorders, seizures, insomnia, hypertension,cardiovascular disease, hyperlipidemia, cancer, such as primary kidneycancer, advanced primary liver cancer, radioactive iodine resistantadvanced thyroid carcinoma, renal cell carcinoma, imatinib-resistantgastrointestinal stromal tumor, mantle cell lymphoma in patients whohave received at least one prior therapy, chronic lymphocyticleukemia/small lymphocytic lymphoma, chronic lymphocytic leukemia/smalllymphocytic lymphoma with 17p deletion, Waldenström's macroglobulinemia,marginal zone lymphoma who require systemic therapy and have received atleast one prior anti-CD20-based therapy, unresectable or metastaticmelanoma with a BRAF V600E or V600K mutation, allergies,transplantation, hormone-refractory metastatic prostate cancerpreviously treated with a docetaxel-containing treatment regimen,hormone-refractory metastatic prostate cancer previously treated with adocetaxel-containing treatment regimen, treatment of clinicallysignificant hypervolemic and euvolemic hyponatremia, including patientswith heart failure and Syndrome of Inappropriate Antidiuretic Hormone(SIADH), prevention of acute and delayed nausea and vomiting associatedwith initial and repeat courses of highly emetogenic cancer chemotherapy(HEC) including high-dose cisplatin, prevention of delayed nausea andvomiting associated with initial and repeat courses of moderatelyemetogenic cancer chemotherapy (MEC), over-active bladder with symptomsof urge urinary incontinence, urgency, and urinary frequency, metastaticnon-small cell lung cancer (NSCLC) whose tumors have epidermal growthfactor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitutionmutations as detected by an FDA-approved test receiving first-line,maintenance, or second or greater line treatment after progression,locally advanced, unresectable or metastatic pancreatic cancer, incombination with gemcitabine, HER2-positive, metastatic breast cancerwho previously received trastuzumab and a taxane, separately or incombination in patients who have either: received prior therapy formetastatic disease or developed disease recurrence during or within sixmonths of completing adjuvant therapy, chronic, accelerated, or blastphase Ph+ chronic myelogenous leukemia (CML) in adults with resistanceor intolerance to prior therapy, gastrointestinal stromal tumor (GIST)after disease progression on or intolerance to imatinib mesylate,advanced renal cell carcinoma (RCC), progressive, well-differentiatedpancreatic neuroendocrine tumors (pNET) in patients with unresectablelocally advanced or metastatic disease, CCR5-tropic HIV-1 infection inpatients 2 years of age and older weighing at least 10 kg in combinationwith other antiretroviral agents, advanced renal cell carcinoma,advanced soft tissue sarcoma who have received prior chemotherapy, manicand mixed episodes associated with Bipolar I, Major Depressive Disorder,irritability associated with Autistic Disorder, Tourette's disorder,agitation associated with schizophrenia or bipolar mania, advanced renalcell carcinoma after failure of one prior systemic therapy, to improveglycemic control in adults with type 2 diabetes mellitus (T2DM) who haveinadequate control with dapagliflozin or who are already treated withdapagliflozin and saxagliptin, progressive, metastatic medullary thyroidcancer (MTC), advanced renal cell carcinoma (RCC) who have receivedprior anti-angiogenic therapy, chronic phase, accelerated phase, orblast phase chronic myeloid leukemia (CML) or Ph+ ALL in adults for whomno other tyrosine kinase inhibitor (TKI) therapy is indicated,T315I-positive CML (chronic phase, accelerated phase, or blast phase) orT315I-positive Philadelphia chromosome in adults, positive acutelymphoblastic leukemia (Ph+ ALL), invasive aspergillosis, invasivemucormycosis, to reduce low-density lipoprotein cholesterol (LDL-C),total cholesterol (TC), apolipoprotein B (apo B), and non-high densitylipoprotein cholesterol (non-HDL-C) in patients with homozygous familialhypercholesterolemia (HoFH), schizophrenia in adults, hormone receptor(HR)-positive, human epidermal growth factor receptor 2 (HER2)-negativeadvanced or metastatic breast cancer in combination with an aromataseinhibitor as initial endocrine based therapy in postmenopausal women, orfulvestrant in women with disease progression following endocrinetherapy, Major Depressive Disorder (MDD), suppression of motor andphonic tics in patients with Tourette's Disorder who have failed torespond satisfactorily to standard treatment, treatment of multiplemyeloma in patients who have received at least two prior therapiesincluding lenalidomide and a proteasome inhibitor and have demonstrateddisease progression on or within 60 days of completion of the lasttherapy, non-small cell lung cancer (NSCLC) whose disease has notprogressed after four cycles of platinum-based first-line chemotherapy,locally advanced or metastatic NSCLC after failure of at least one priorchemotherapy regimen, locally advanced, unresectable or metastaticpancreatic cancer, overactive bladder with symptoms of urge urinaryincontinence, urgency, and urinary frequency, advanced renal cellcarcinoma (RCC) after failure of treatment with sunitinib or sorafenib,subependymal giant cell astrocytoma (SEGA) associated with tuberoussclerosis (TS) who require therapeutic intervention but are notcandidates for curative surgical resection, renal angiomyolipoma,tuberous sclerosis complex, hormone receptor (HR)-positive, humanepidermal growth factor receptor 2 (HER2)-negative advanced ormetastatic breast cancer with disease progression following endocrinetherapy in women in combination with fulvestrant, as monotherapy for thetreatment of adult patients with HRpositive, HER2-negative advanced ormetastatic breast cancer with disease progression following endocrinetherapy and prior chemotherapy in the metastatic setting, cysticfibrosis (CF) in patients age 2 years and older who have one mutation inthe CFTR gene that is responsive to ivacaftor based on clinical and/orin vitro assay data, deleterious or suspected deleterious germlineBRCA-mutated advanced ovarian cancer in adult patients who have beentreated with three or more prior lines of chemotherapy, intermediate orhigh-risk myelofibrosis, including primary myelofibrosis,post-polycythemia vera myelofibrosis and post-essential thrombocythemiamyelofibrosis, polycythemia vera patients who have had an inadequateresponse to or are intolerant of hydroxyurea, as an adjunctive therapyto antidepressants for the treatment of major depressive disorder (MDD),schizophrenia, cystic fibrosis (CF) patients aged 12 years and older whoare homozygous for the F508del mutation or who have at least onemutation in the cystic fibrosis transmembrane conductance regulator(CFTR) gene that is responsive to tezacaftor/ivacaftor based on in vitrodata and/or clinical evidence, metastatic colorectal cancer (CRC)patients who have been previously treated with fluoropyrimidine-,oxaliplatin- and irinotecan-based chemotherapy, an antiVEGF therapy,and, if RAS wild-type, an anti-EGFR therapy, locally advanced,unresectable or metastatic gastrointestinal stromal tumor (GIST)patients who have been previously treated with imatinib mesylate andsunitinib malate, hepatocellular carcinoma (HCC) who have beenpreviously treated with sorafenib, chronic HCV genotype 1 or 3 infectionwith sofosbuvir and with or without ribavirin, metastatic non-small celllung cancer (NSCLC) in patients whose tumors are anaplastic lymphomakinase (ALK) or ROS1-positive as detected by an FDA-approved test,opioid induced constipation (OIC) in adult patients with chronicnon-cancer pain, including patients with chronic pain related to priorcancer or its treatment who do not require frequent (e.g., weekly)opioid dosage escalation, unresectable or metastatic melanoma inpatients with BRAF V600E mutation as detected by an FDA-approved test,in combination with trametinib, for the treatment of unresectable ormetastatic melanoma in patients with BRAF V600E or V600K mutations asdetected by an FDA-approved test, melanoma in patients with BRAF V600Eor V600K mutations, as detected by an FDA-approved test, and involvementof lymph node(s), following complete resection, metastatic non-smallcell lung cancer (NSCLC) in patients with BRAF V600E mutation asdetected by an FDA-approved test, locally advanced or metastaticanaplastic thyroid cancer (ATC) in patients with BRAF V600E mutation andwith no satisfactory locoregional treatment options, with or withoutribavirin for treatment of chronic HCV genotypes 1 or 4 infection inadults, the treatment of patients with non-metastaticcastration-resistant prostate cancer, the treatment of patients withanaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lungcancer (NSCLC) who have progressed on or are intolerant to crizotinib,the treatment of seizures associated with Lennox-Gastaut syndrome orDravet syndrome in patients 2 years of age and older, the treatment ofadult patients with relapsed follicular lymphoma (FL) who have receivedat least two prior systemic therapies, the treatment of adult patientswith relapsed or refractory chronic lymphocytic leukemia (CLL) or smalllymphocytic lymphoma (SLL) after at least two prior therapies, thetreatment of adult patients with relapsed or refractory follicularlymphoma (FL) after at least two prior systemic therapies, incombination with binimetinib, for the treatment of patients withunresectable or metastatic melanoma with a BRAF V600E or V600K mutation,as detected by an FDA-approved test, the treatment of premenopausalwomen with acquired, generalized hypoactive sexual desire disorder(HSDD) as characterized by low sexual desire that causes marked distressor interpersonal difficulty and is not due to a co-existing medical orpsychiatric condition, problems within the relationship, or the effectsof a medication or other drug substance, to reduce the risk ofhospitalization for worsening heart failure in patients with stable,symptomatic chronic heart failure with left ventricular ejectionfraction ≤35%, who are in sinus rhythm with resting heart rate ≥70 beatsper minute and either are on maximally tolerated doses of beta-blockersor have a contraindication to beta-blocker use, the treatment of adultpatients with relapsed or refractory acute myeloid leukemia (AML) with asusceptible IDH1 mutation as detected by an FDA-approved test, thetreatment of patients with multiple myeloma who have received at least 2prior regimens, including bortezomib and an immunomodulatory agent, thetreatment of adult patients with locally advanced basal cell carcinoma(BCC) that has recurred following surgery or radiation therapy, or thosewho are not candidates for surgery or radiation therapy, the treatmentof patients with unresectable or metastatic melanoma with BRAF V600Emutation as detected by an FDA-approved test, and the treatment ofpatients with Erdheim-Chester Disease with BRAF V600 mutation.

14. The method of any of embodiments 1A-1B, 2A-2B, 3A-3B, 4A-4B, 5A-5B,6A-6B, 7, 8, 11, or 12, wherein the patient is treated for a disease orcondition selected from the group consisting of: non-metastaticcastration-resistant prostate cancer; anaplastic lymphoma kinase(ALK)-positive metastatic non-small cell lung cancer (NSCLC) who haveprogressed on or are intolerant to crizotinib; seizures associated withLennox-Gastaut syndrome or Dravet syndrome in patients 2 years of ageand older; relapsed follicular lymphoma (FL) in adults who have receivedat least two prior systemic therapies; adults with relapsed orrefractory chronic lymphocytic leukemia (CLL) or small lymphocyticlymphoma (SLL) after at least two prior therapies; adult patients withrelapsed or refractory follicular lymphoma (FL) after at least two priorsystemic therapies, in combination with binimetinib; unresectable ormetastatic melanoma with a BRAF V600E or V600K mutation, as detected byan FDA-approved test, the treatment of premenopausal women withacquired, generalized hypoactive sexual desire disorder (HSDD) ascharacterized by low sexual desire that causes marked distress orinterpersonal difficulty and is not due to a co-existing medical orpsychiatric condition, problems within the relationship, or the effectsof a medication or other drug substance, to reduce the risk ofhospitalization for worsening heart failure in patients with stable,symptomatic chronic heart failure with left ventricular ejectionfraction ≤35%, who are in sinus rhythm with resting heart rate ≥70 beatsper minute and either are on maximally tolerated doses of beta-blockersor have a contraindication to beta-blocker use; adult patients withrelapsed or refractory acute myeloid leukemia (AML) with a susceptibleIDH1 mutation as detected by an FDA-approved test; multiple myeloma whohave received at least 2 prior regimens, including bortezomib and animmunomodulatory agent; adult patients with locally advanced basal cellcarcinoma (BCC) that has recurred following surgery or radiationtherapy, or those who are not candidates for surgery or radiationtherapy; unresectable or metastatic melanoma with BRAF V600E mutation asdetected by an FDA-approved test; Erdheim-Chester Disease with BRAF V600mutation; non-metastatic castration-resistant prostate cancer;anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lungcancer (NSCLC) who have progressed on or are intolerant to crizotinib;seizures associated with Lennox-Gastaut syndrome or Dravet syndrome inpatients 2 years of age and older; adult patients with relapsedfollicular lymphoma (FL) who have received at least two prior systemictherapies; adult patients with relapsed or refractory chroniclymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) after atleast two prior therapies; adult patients with relapsed or refractoryfollicular lymphoma (FL) after at least two prior systemic therapies, incombination with binimetinib, for the treatment of patients withunresectable or metastatic melanoma with a BRAF V600E or V600K mutation,as detected by an FDA-approved test; premenopausal women with acquired,generalized hypoactive sexual desire disorder (HSDD) as characterized bylow sexual desire that causes marked distress or interpersonaldifficulty and is not due to a co-existing medical or psychiatriccondition, problems within the relationship, or the effects of amedication or other drug substance; to reduce the risk ofhospitalization for worsening heart failure in patients with stable,symptomatic chronic heart failure with left ventricular ejectionfraction ≤35%, who are in sinus rhythm with resting heart rate ≥70 beatsper minute and either are on maximally tolerated doses of beta-blockersor have a contraindication to beta-blocker use; adult patients withrelapsed or refractory acute myeloid leukemia (AML) with a susceptibleIDH1 mutation as detected by an FDA-approved test; patients withmultiple myeloma who have received at least 2 prior regimens, includingbortezomib and an immunomodulatory agent, the treatment of adultpatients with locally advanced basal cell carcinoma (BCC) that hasrecurred following surgery or radiation therapy, or those who are notcandidates for surgery or radiation therapy; patients with unresectableor metastatic melanoma with BRAF V600E mutation as detected by anFDA-approved test; and the treatment of patients with Erdheim-ChesterDisease with BRAF V600 mutation.

15. The method of any one of embodiments 1A-14, wherein the waiting instep (c) is at least 5 days.

16. The method of any one of embodiments 1A-14, wherein the waiting instep (c) is at least 7 days.

17. The method of any one of embodiments 1A-14, wherein the waiting instep (c) is at least 14 days.

18. The method of any one of embodiments 1-14, wherein the waiting instep (c) is in the range of from 2-42 days.

19. The method of any one of embodiments 1-12, wherein the waiting instep (c) is in the range of from 5-42 days.

20. The method of any one of embodiments 1-13, wherein the waiting instep (c) is in the range of from 7-21 days.

21. The method of any one of embodiments 1-13, wherein the waiting instep (b) is in the range of from 14-28 days.

22. The method of any one of embodiments 1A-21, wherein the referencedose of the CYP3A4 substrate drug is administered or a reduced dose ofthe CYP3A4 substrate drug is administered.

EXAMPLES Example 1. Pharmacokinetic Studies with Posaconazole andLurasidone

Inventors studied 6 obese male and female subjects (ages 18-50, BMI>35)taking Posaconazole oral tablets (300 mg qd) and Lurasidone (20 mg qd).Body weights and BMI measurements for the 6 subjects are provided belowin Table 1.

TABLE 1 Subject Demographics Subject # Weight (kg) BMI (kg/m²) 101-001111.8 45 101-002 136.8 44.4 101-005 137.7 51.2 101-007 103.7 36.8101-008 122.3 39.8 101-010 120.0 43.9

Subjects were dosed with Lurasidone alone on Day 1, then subsequentlydosed to steady-state Posaconazole levels, with a loading dose of 300 mgtwice a day on Day 2 and 300 mg once a day thereafter over a period of14 days. Posaconazole administration was then stopped and Lurasidone (20mg qd) administered 2, 4, and 6 days after administration had ceased(studies days 17, 19, and 21 respectively). Lurasidone AUC was measuredfor 24 hours after each administration. Table 2 shows subject LurasidoneAUC levels 2, 4 and 6 days after Posaconazole was stopped, PosaconazoleAUC levels 2, 4, and 6 days after Posaconazole was stopped, and theratio of post-Posaconazole Lurasidone AUC to the baseline Lurasidone AUCmeasured before Posaconazole treatment:

TABLE 2 Lurasidone AUC Ratio Subject Data Lurasidone AUC (ng*h/mL)Posaconazole AUC (ng*h/mL) relative to Day 1 BMI Weight Subject Day 1Day 17 Day 19 Day 21 Day 17 Day 19 Day 21 Day 17 Day 19 Day 21 (kg/m²)(kg) HMS001 101-001 92.8 284 234.4 204.5 2886 2019 1365 3.06 2.53 2.2045.0 111.8 DES005 101-005 26 167.3 186 168 2512 1954 1563 6.43 7.15 6.4651.2 137.7 TRB007 101-007 38.3 173.8 89.5 124.7 824 542 285 4.54 2.343.26 36.8 103.7 NNJ010 101-010 71 211.7 163 226 4551 3688 3081 2.98 2.303.18 43.9 120.0 KDH002 101-002 110 195.5 146 186.3 1299 626 284 1.781.33 1.69 44.4 136.8 DTG008 101-008 45.6 57 36.2 27.8 190 78 31 1.250.79 0.61 39.8 122.3

Table 3 compares Lurasidone AUC levels after Posaconazole treatment tobaseline Lurasidone AUC levels.

TABLE 3 Lurasidone Levels vs. Base Line Days After Posaconazole WasCeased Day 2 Day 4 Day 6 Mean 3.3x 2.7x 2.9x Min 1.3x 0.8x 0.6x Max 6.4x7.2x 6.5x Median 3.0x 2.3x 2.7x

As shown above in Table 3, the post-Posaconazole treatment mean AUCratios of Lurasidone are about 3 times higher than the baseline. Thisdata indicates that Posaconazole accumulates in obese subjects, andresults in significantly higher Lurasidone AUC levels compared tobaseline levels measured before Posaconazole treatment.

The AUC measurements from two patients (DTG008 and KDH002) indicatesthat these patients were non-compliant with the Posaconazole treatmentregimen, and the corresponding AUC measurements were removed from thestudy. The results are shown below in Table 4.

TABLE 4 Lurasidone Levels vs. Base Line Days After Posaconazole WasCeased Excluding DTG008 & KDH002 Day 2 Day 4 Day 6 Mean 4.3x 3.6x 3.8xMin 3.0x 2.3x 2.2x Max 6.4x 7.2x 6.5x Median 3.8x 2.4x 3.2x

These results indicate that post-Posaconazole treatment mean AUC ratiovalues for Lurasidone are in the range of from 3.6-4.3× for 2-6 daysafter ceasing Posaconazole treatment.

In conclusion, the results from the clinical trials reported in Example1 indicate that the Posaconazole accumulates in the body of obesepatients after treatment has stopped, and patients should delay a firstdose of Lurasidone or reduce the first dose of Lurasidone to achievesafe blood plasma levels of Lurasidone.

Example 2. Sustained Impairment of Lurasidone Clearance afterDiscontinuation of Posaconazole. Impact of Obesity, and Implications forPatient Safety

The following studies were reported by Greenblatt et al., J. Clin.Psychopharmacol., 2018; 38(4):289-295 (doi:10.1097/JCP.0000000000000892), which is herein incorporated by referencein its entirety for all purposes.

The antipsychotic agent lurasidone is metabolized by Cytochrome P450-3A(CYP3A) enzymes. Coadministration with strong CYP3A inhibitors (such asketoconazole, posaconazole, and ritonavir) is contraindicated due to therisk of sedation and movement disorders from high levels of lurasidone.This study evaluated the time-course of recovery from the posaconazoledrug interaction, and the effect of obesity on the recovery process.

With posaconazole coadministration, lurasidone area under theconcentration curve (AUC) increased by an arithmetic mean factor of 6.2in normals, and by 4.9 in obese subjects. Post-treatment washout ofposaconazole was slow in normals (mean half-life 31 hours), and furtherprolonged in obese subjects (53 hours). Recovery of lurasidone AUCtoward baseline was correspondingly slow, and was incomplete. AUCremained significantly elevated above baseline both in normals (factorof 2.1) and obese subjects (factor of 3.4) even at 2 weeks afterstopping posaconazole.

Product labeling does not address the necessary delay afterdiscontinuation of a strong CYP3A inhibitor before lurasidone can besafely administered. It is recommended that normal-weight and obesepatients be required to limit the dosage of lurasidone, or undergo awashout period after discontinuation of posaconazole, as set forth inthe present disclosure.

Methods. Study Site and Institutional Review Board. The study wasconducted at Avail Clinical Research, located in DeLand, Fla. The studyprotocol and consent document were reviewed and approved by IntegReview,Austin, Tex. All study participants provided written informed consentprior to initiation of any study procedures. In addition, this study wasperformed in accordance with the Declaration of Helsinki, InternationalConference on Harmonization Good Clinical Practice guidelines, andapplicable regulatory requirements.

Subjects. The study participants consisted of two cohorts, with a totalof 34 subjects receiving at least one dose of study drug, and a total of24 subjects completing the entire study with evaluable pharmacokineticdata. In the first cohort were those of normal body habitus (n=11completed; BMI 18.5-24.9 kg/m², inclusive); the second group consistedof subjects of obese body habitus (n=13 completed; BMI≥35 kg/m²).Subjects were previously known to the research center, or were recruitedthrough notices in the public media. Subjects were matched by gender andage when possible. Sample sizes were based on power calculations.

Potential participants underwent screening and evaluation within 30 daysof study initiation. Procedures included medical and psychiatrichistory, physical examination, electrocardiogram if indicated,hematologic and biochemical screening (including liver function testssuch as alanine transaminase, asparagine transaminase, and bilirubin),and urine testing for drugs of abuse. All study participants werehealthy, active, non-smoking adults with no history of significantmedical or psychiatric disease and taking no prescription medications.Obese subjects were free of metabolic or other complications of obesity.Potentially child-bearing women in both groups had negative pregnancytests and agreed to avoid the risk of pregnancy during the course of thestudy. Subjects were instructed to avoid alcohol use throughout thecourse of the study and underwent a breath alcohol analysis prior toinitiation of the study protocol.

Subjects' waist circumference was measured manually. Percent android fatfor all subjects was determined by dual energy X-ray absorptiometry(DXA). For three subjects whose weight exceeded the limits of the DXAinstrumentation, percent android fat was imputed using population dataavailable from the National Health and Nutrition Evaluation Survey(NHANES). Total android fat (termed total body fat) was calculated asthe product of body weight and percent android fat. Ideal body weight(IBW) was determined from actuarial data based on height and gender, andpercent ideal body weight calculated as the ratio of actualweightdivided by IBW.

Procedures. Subjects received lurasidone (20 mg tablet) on the morningsof study Days 1, 14, 20, 23, 26, and 30. Lurasidone doses were givenimmediately prior to a continental breakfast provided in the clinicalresearch unit. Venous blood samples were drawn intoethylenediaminetetraacetic acid (EDTA)-containing tubes from anindwelling catheter, or by separate venipuncture, prior to thelurasidone dose and at 1, 2, 3, 4, 8, 12, 18, 24, 48, and 72 hourspost-dose. Samples were centrifuged and the plasma was separated andfrozen at −70° C. until the time of assay.

On study Day 4, subjects received two doses of posaconazole (300 mgBID). On the mornings of Days 5-17, they received posaconazole 300 mgonce daily. As posaconazole is to be taken with food, subjects were feda continental breakfast in the clinical research unit after receivingposaconazole and prior to discharge from the unit. Venous blood sampleswere drawn into EDTA containing tubes prior to the posaconazole dose onDays 4, 7, 11, and prior to the lurasidone dose on Days 14, 20, 23, 26and 30. An additional blood sample was taken 5 hours after posaconazoledosage on Day 17, for approximate determination of maximum posaconazoleplasma concentrations, and on Day 33. Samples were centrifuged and theplasma was separated and frozen at −70° C. until the time of assay.

Analytic Methods. All bioassay analyses were performed by KeystoneBioanalytical, North Wales, Pa. For analysis of posaconazole, theinternal standard (posaconazole-D4) was added to the biological samples.Plasma samples were precipitated using formic acid in acetonitrile andisolated using a Phree phospholipid removal tube. An aliquot of thesample was injected onto a high-pressure liquid chromatograph withtandem mass spectrometry triple quadrupole mass spectrometer (SCIEXAPI-5500). The analytical column was a Unison CK-218, 3 m particle sizeHPLC column (50×2 mm) from Imtakt USA (Portland, Oreg.). The mobilephase consisted of an aqueous component (0.25% formic acid and 10 mMammonium formate in water) and an organic component (0.1% formic acid inacetonitrile) and was delivered by gradient, with the organic componentgoing from 35% to 100%. The m/z transitions monitored were 701.6 >614.4for posaconazole and 705.6 >618.4 for the internal standard. Thecalibration curve ranged from 1-1000 ng/mL (8 concentrations induplicate).

For analysis of lurasidone, the internal standard (lurasidone-D8) wasadded to the biological samples. Plasma samples were isolated using aPhree phospholipid removal tube. An aliquot of the sample was injectedonto a high-pressure liquid chromatograph with tandem mass spectrometrytriple quadrupole mass spectrometer (SCIEX API-5500). The analyticalcolumn was a Unison UK-C18, 3 μm particle size HPLC column (50×2 mm)from Imtakt USA (Portland, Oreg.). The mobile phase consisted of anaqueous component (0.025% formic acid and 10 mM ammonium formate inwater) and an organic component (0.1% formic acid in acetonitrile) andwas delivered by gradient, with the organic component going from 35% to100%. The m/z transitions monitored were 493.4>166.1 for lurasidone and501.4>166.1 for the internal standard. The calibration curve ranged from0.25-200 ng/mL (8 concentrations in duplicate).

Pharmacokinetic and Statistical Methods. For each subject, pre-doseplasma posaconazole concentrations on study Days 14 and 17 wereaveraged, and used as a steady-state concentration (C_(ss)) to calculateapparent steady-state clearance of posaconazole according to therelation: Clearance=(dosing rate)/C_(ss). The apparent washout half-lifeof posaconazole was calculated by log-linear regression analysisstarting with the plasma concentration on Day 20 and ending with thelast non-zero value. Differences between normal-weight and obese cohortswere evaluated by Student's t-test for independent groups. The relationbetween measures of body habitus and posaconazole washout half-life forindividual subjects was evaluated by linear regression analysis.

For each lurasidone trial for each subject, the terminal log-linearphase of the plasma concentration curve was identified visually, and theterminal rate constant (beta) was determined by log-linear regressionanalysis. This was used to calculate the elimination half-life. Areaunder the plasma concentration curve from time zero until the lastnon-zero point was determined by the linear trapezoidal method. To thiswas added the residual area, calculated as the final non-zeroconcentration divided by beta, yielding the total area under the plasmaconcentration curve extrapolated to infinity (AUC). Also tabulated wasthe observed maximum plasma concentration (C_(max)). AUC and C_(max)both were adjusted, where necessary, for non-zero baseline (pre-dose)concentrations measured in some subjects on the Day 20, 23, 26, and 30trials.

Variables were aggregated as arithmetic mean and SD or SE. LurasidoneC_(max) and AUC were also aggregated as geometric mean and 90%confidence interval (90% CI). Differences in kinetic variables betweenstudy Day 1 and Days 14, 20, 23, 26, and 30 (control vs afterposaconazole administration) were evaluated either from theuntransformed data using Dunnett's t-test, or by comparison of geometricmeans and the 90% CI of the difference.

The relation between lurasidone AUC and plasma posaconazoleconcentration for individual subjects across the 5 DDI trials (Days 14,20, 23, 26, and 30) was analyzed by nonlinear regression (SAS PROCNLIN). The following function was fitted to data points:

Y=Y ₀ +BX ^(A)

where Y is the lurasidone AUC value corresponding to X, the plasmaposaconazole concentration at the start of relevant AUC measurementperiod. Iterated variables were: Y₀, A, and B.

Results

Subject Characteristics. Screening procedures yielded 34 subjects whowere potential study participants. Of these, 8 initiated participationbut did not complete the study for personal or administrative reasonsnot related to the study or study medications. Data from 2 othersubjects could not be analyzed due to apparent protocol deviations. Atotal of 24 subjects (11 normal-weight and 13 obese) completed the studyand were included in the pharmacokinetic analysis (Table 5). The groupswere comparable in age, gender composition, height, and IBW. The obesegroup had significantly higher values of weight, percent IBW, BMI, waistcircumference, percent android fat, and total body (android) fat (Table5). The mean weight in the obese group s 140 kg (309 pounds), and themean BMI was 49.3 kg.

TABLE 5 DEMOGRAPHIC CHARACTERISTICS OF STUDY PARTICIPANTS IndependentNormal- t-test: Normal weight* Obese* vs obese Number 11 13 Age (years)34 ± 8 33 ± 7 N.S. Male/female 6/5 6/7 Weight (Kg) 67.9 ± 9.1 140.4 ±32   P < 0.001 (Pounds) 149 ± 29 309 ± 70 P < 0.001 Height (Cm) 171 ± 10168 ± 11 N.S. (Inches) 67.3 ± 4.0 66.3 ± 4.3 N.S. BMI (kg/m²) 23.1 ± 1.849.3 ± 9.6 P < 0.001 Waist circumference (Cm) 80.4 ± 6.8 129.3 ± 22.4 P< 0.001 (Inches) 31.7 ± 2.7 50.9 ± 8.8 P < 0.001 Ideal body weight (kg) 64.5 ± 12.3  61.9 ± 11.4 N.S. Percent ideal body weight 106 ± 11 230 ±46 P < 0.001 Percent android fat  33 ± 12 66 ± 4 P < 0.001 Total bodyfat (kg) 22.5 ± 8.0  81.3 ± 25.8 P < 0.001 *Mean ± SD

Adverse Events. Five subjects experienced adverse events consideredpossibly or probably related to one or both study medications. Thesewere gastrointestinal disturbances in two cases, and one each of drymouth, somnolence, and headache. All resolved without specifictreatment.

Posaconazole Pharmacokinetics. Plasma posaconazole concentrations hadreached steady-state by study Day 14 (FIG. 1). Mean C_(ss) wassignificantly lower, and posaconazole clearance was significantlyhigher, in the obese cohort compared to controls (Table 6). However,weight-normalized posaconazole clearance was not significantly differentbetween the groups.

Washout of posaconazole after discontinuation of treatment wassignificantly slower in the obese group compared to controls (P<0.005)(FIG. 1). Mean washout half-life values in the two groups were 2.19 days(52.5 hours) and 1.28 days (31 hours), respectively (Table 6). Among allsubjects, the correlation between posaconazole washout half-life andeach of the measures of body habitus was statistically significant, butthe degree of obesity explained only a small fraction of variance inwashout half-life (r2<0.32). The attenuated associations were in partattributable to two obese subjects with very long half-life values (121hours).

TABLE 6 POSACONAZOLE PHARMACOKINETICS Value of Student's t: Mean ± SDvalue for Group: Normal Normal Obese vs Obese Steady-state 2377 ± 11881462 ± 649   3.33 (P < 0.005) concentration (ng/mL) Steady-stateclearance mL/min 101 ± 71  175 ± 91  2.19 (P < 0.04) mL/min/kg 1.48 ±1.02 1.25 ± 0.61 N.S. Washout half-life  31 ± 6.7 52.5 ± 31.1 2.25 (P <0.04) (hours)

Lurasidone Pharmacokinetics. Coadministration of lurasidone withposaconazole resulted in a highly significant increase in lurasidoneC_(max) and AUC (FIG. 2, Table 7). Comparing Day 14 values to the Day 1pre-posaconazole values based on ratio of geometric means, C_(max)increased by a factor of 4.0 in normal-weight subjects and by 2.9 in theobese subjects. Corresponding increases in AUC were greater thanincreases in C_(max). Geometric mean AUC increased by a factor of 5.75in the normal-weight cohort, and by 4.34 in the obese cohort (Table 7).When calculated as arithmetic mean ratios, values were 6.2 in controlsand 4.9 in obese subjects.

TABLE 7 SUMMARY OF LURASIDONE PHARMACOKINETICS Arithmetic mean ±standard error Geometric mean (90% CI) Ratio of geometric means (RGM) vsDay 1 (90% CI) Corrected Cmax (ng/mL) Corrected Cmax (ng/mL) CorrectedCmax Normal Obese Normal Obese Normal Obese Day 1 17.1 ± 1.6 19.8 ± 416.3 (13.5-19.6) 15.1 (10.2-22.6) Day 14  69.4 ± 8.3*  47.0 ± 5* 65.2(53.5-79.5) 44.1 (35.9-54.2) Day 14 4.00 (3.09-5.19) 2.91 (1.89-4.47)Day 20  55.9 ± 7.8*  40.0 ± 5* 48.6 (34.6-68.4) 36.6 (29-46.3) Day 202.98 (2.06-4.33) 2.42 (1.55-3.76) Day 23  42.5 ± 6.3* 30.0 ± 3 37.8(28.5-50.2) 28.0 (22.7-34.6) Day 23 2.32 (1.68-3.21) 1.85 (1.2-2.84) Day26 32.2 ± 6.6 30.0 ± 4 26.5 (18.3-30.9) 26.9 (21-34.5) Day 26 1.63(1.1-2.4) 1.78 (1.13-2.79) Day 30 26.2 ± 3.2   25.0 ± 4.4 24.0(18.6-30.9) 21.6 (16.4-28.4) Day 30 1.47 (1.09-1.99) 1.42 (0.89-2.26)Total AUC (ng/mL × hr) Total AUC (ng/mL × hr) Total AUC Normal ObeseNormal Obese Normal Obese Day 1 57.9 ± 5.8  50.8 ± 9   54.5 (43.3-68.6)42.0 (30.4-57.9) Day 14 333 ± 24* 205 ± 19* 324 (282-372) 195 (166-230)Day 14 5.94 (4.64-7.46) 4.66 (3.28-6.59) Day 20 265 ± 34* 217 ± 20* 237(175-321) 205 (173-244) Day 20 4.34 (3-6.28) 4.90 (3.45-6.96) Day 23 204± 27* 170 ± 17* 184 (139-242) 160 (133-193) Day 23 3.38 (2.39-4.78) 3.82(2.68-5.47) Day 26 148 ± 27* 152 ± 19* 122 (83-179) 140 (113-173) Day 262.24 (1.45-3.46) 3.33 (2.3-4.83) Day 30 129 ± 20* 150 ± 17* 114 (85-154)140 (116-170) Day 30 2.10 (1.46-3.01) 3.34 (2.33-4.78) *P < 0.05compared to Day 1 value, Dunnett's t test

Kinetic variables for lurasidone recovered toward the pre-posaconazolebaseline values during the posaconazole washout period. Based on ratiosof geometric mean values versus the Day 1 baseline, C_(max) remainedelevated above Day 1 even on Day 30 (ratio=1.47, 90% CI=1.09-1.99) inthe normal-weight control subjects. In the obese cohort, C_(max)remained above baseline up to Day 26. Recovery of AUC in both groups waseven less complete, with Day 30 ratios of 1.9 in the normal-weight groupand 2.8 in the obese subjects (arithmetic mean ratios: 2.1 and 3.4,respectively). Consistent with the slower washout of posaconazole in theobese group, the rate of recovery of lurasidone AUC toward baselinevalues was correspondingly slower in the obese cohort compared tocontrols (FIG. 3).

Baseline values of lurasidone elimination half-life averaged 9.4 hoursin normal-weight subjects and 10.9 hours in the obese group. Thesevalues are in the range of what has been reported previously. Thehalf-life values were significantly prolonged during and afteradministration of posaconazole, and were still substantially longer thanbaseline values even on the Day 30 trial (FIG. 2, Table 8). Meanhalf-life values were longer in obese subjects compared to controls.However, half-life determinations were complicated by estimates thatexceeded the sampling duration in some subjects.

TABLE 8 LURASIDONE ELIMINATION HALF-LIFE (HOURS) Arithmetic mean ± S.E.Normal Obese Day 1 9.4 ± 1.5 10.9 ± 4   Day 14 37 ± 4* 38 ± 2* Day 20 39± 3* 48 ± 4* Day 23 48 ± 5* 52 ± 3* Day 26 50 ± 7* 61 ± 4* Day 30 45 ±9* 71 ± 5* *P < 0.05 compared to Day 1 based on Dunnett's t test

Relation of Plasma Posaconazole to Lurasidone AUC. Based on analysis ofdata from all subjects, individual variations in plasma posaconazoleconcentrations accounted for 66% of the variance in lurasidone AUC atthe corresponding times (r²=0.66), indicating that posaconazole exposureis a principal determinant of the magnitude of theposaconazole-lurasidone DDI (FIG. 4).

Discussion. The present study evaluated the pharmacokinetic DDI betweenlurasidone as victim (substrate) and the strong CYP3A inhibitorposaconazole as perpetrator (precipitant), both in volunteers of normalbody weight and in an otherwise healthy group of subjects with BMI≥35kg/m2. A particular focus of the study was the time-course of recoveryfrom the DDI during the two weeks after discontinuation of posaconazole.

Coadministration of lurasidone with typical doses of posaconazoleresulted in increased lurasidone exposure (total AUC) by a factoraveraging in the range of 4 to 6 in both groups of subjects. Afterposaconazole was discontinued, the effect on lurasidone exposure did notreturn quickly to baseline. Rather, the DDI persisted for at least 2weeks after the last dose of posaconazole, and probably well beyond thestudy duration. The slow recovery from the DDI was consistent with thelong elimination half-life of posaconazole. With all data aggregated,plasma posaconazole concentration accounted for 66% of the variabilityin lurasidone AUC associated with the DDI.

The pharmacokinetic properties of posaconazole were significantlymodified in the cohort of obese subjects compared to those of normalbody size. The clearance of posaconazole—not corrected for bodyweight—was higher in obese subjects compared to controls, resulting inlower values of C_(ss) when the same daily dosage was administered toboth groups. Despite the higher clearance, the washout half-life wassignificantly prolonged in the obese subjects compared to controls. Thisis likely explained by the disproportionate distribution of thelipophilic drug posaconazole into excess adipose tissue, thereby causinga prolongation of elimination half-life. As a result of the longerhalf-life and persistence of posaconazole in blood, the duration of thelurasidone DDI was correspondingly longer. At two weeks after the lastdose of posaconazole, lurasidone AUC was still elevated above baselineby a mean factor of 3.3 in the obese subject group.

This study involved a relatively small number of subjects, but thefindings were statistically robust. Although lurasidone was administeredas single test doses, the kinetics of lurasidone are linear, andsingle-dose kinetic properties will be predictive of behavior duringmultiple dosing as is customary in the treatment of schizophrenia.

Conclusions. The posaconazole-lurasidone DDI persists long afterposaconazole is discontinued, resulting in a sustained risk of apotentially hazardous DDI. The duration of persistent risk is furtherprolonged in obese individuals due to the effect of obesity on theelimination kinetics of posaconazole. Revision of product labeling isneeded to assure patient safety. Based on the findings of this study, itis recommended to require normal-weight and obese patients to limit thedosage of lurasidone, or undergo a washout period, as set forth in thepresent disclosure.

Example 3. Persistence of a Posaconazole-Mediated Drug-Drug Interactionwith Ranolazine after Cessation of Posaconazole Administration: Impactof Obesity and Implications for Patient Safety

The following studies were reported by Chow et al., J. Clin.Pharmacology. 2018; 0(0):1-7 (doi: 10.1002/jcph.1257), which is hereinincorporated by reference in its entirety for all purposes.

The antianginal agent ranolazine is metabolized primarily by cytochromeP450-3A (CYP3A) enzymes. Coadministration with strong CYP3Ainhibitors,such as ketoconazole and posaconazole, is contraindicated due to risk ofQT prolongation from high levels of ranolazine. This study evaluated thetime course of recovery from the posaconazole drug interaction innormal-weight and otherwise healthy obese subjects. Subjects receivedsingle doses of ranolazine in the baseline control condition, againduring coadministration of posaconazole, and at 4 additional time pointsduring the 2 weeks after posaconazole discontinuation. With posaconazolecoadministration, the geometric mean ratio of ranolazine area under theconcentration curve (AUC) increased by a factor of 3.9 in normals and by2.8 in obese subjects. Posttreatment washout of posaconazole was slow innormals (mean half-life 36 hours) and further prolonged in obesesubjects (64 hours). Recovery of ranolazine AUC toward baseline wasdelayed. AUC remained significantly elevated above baseline innormal-weight and obese subjects for 7-14 days after stoppingposaconazole. Current product labeling does not address the need fordelay or a reduced dose of ranolazine after discontinuation of a strongCYP3A inhibitor before ranolazine can be safely administered. It isrecommended that administration of ranolazine should be limited, forexample to 500 mg twice daily for 7 days after posaconazolediscontinuation in patients with body mass index 18.5-24.9 kg/m² and for12 days in patients with body mass index ≥35 kg/m² after ranolazine isresumed.

Methods. Study Site and Institutional Review Board. The study wasconducted at Avail Clinical Research, located in DeLand, Fla. The studyprotocol and consent document were reviewed and approved by IntegReview,Austin, Tex. All study participants provided written informed consentprior to initiation of any study procedures. In addition, this study wasperformed in accordance with the Declaration of Helsinki, InternationalConference on Harmonisation Good Clinical Practice guidelines, andapplicable regulatory requirements.

Subjects. A total of 30 subjects, aged 19 to 50, were enrolled in thestudy (Table 9). All were healthy adults without evidence of activemedical disease, with the exception of obesity, and taking noprescription medications; 43% of the study subjects were male.

The study included 2 cohorts of volunteers. The first consisted ofsubjects of normal body habitus (BMI 18.5-24.9 kg/m, inclusive, n 15);the second consisted of subjects of obese body habitus (BMI 2:35 kg/m²,n 15). Subjects were matched by sex and age when possible. Sample sizeswere based on power calculations.

Potential study participants underwent screening and evaluation within30 days of study initiation. Procedures included medical and psychiatrichistory, physical examination, electrocardiogram (ECG), hematologic andbiochemical screening, and urine testing for drugs of abuse. All studyparticipants were healthy active nonsmoking adults with no history ofsignificant medical or psychiatric disease and taking no prescriptionmedications. Obese subjects were free of metabolic or othercomplications of obesity. Potentially child-bearing women in both groupshad a negative pregnancy test and agreed to avoid the risk of pregnancyduring the course of the study. Subjects were also administered 12-leadECGs in triplicate on study days 1 and 15 before and 4 hours after theranolazine dose as well as before discharge on day 30.

Subjects' waist circumference was measured manually. Percentage androidfat for all subjects was determined by dual-energy x-ray absorptiometry.Total android fat (total body fat) was calculated as the product of bodyweight and percentage android fat.

Procedures. Subjects received ranolazine (500 mg extended-releasetablet) on the mornings of study days 1, 15, 18, 22, 25, and 29. Venousblood samples were drawn into ethylenediaminetetraacetic acid(EDTA)-containing tubes from an indwelling catheter or by separatevenipuncture prior to the ranolazine dose and at 1, 2, 4, 6, 8, 12, 18,24, and 32 hours postdose. Samples were centrifuged, and the plasma wasseparated and frozen at −70° C. until the time of assay of plasmaranolazine concentrations.

On study day 2, subjects received posaconazole (300 mg delayed-releasetablet twice a day), and on the mornings of days 3-15, subjects receivedposaconazole (300 mg delayed-release tablet daily). Because posaconazoleis to be taken with food,⁶ subjects were fed a continental breakfast inthe clinical research unit after receiving posaconazole and beforedischarge from the unit. Venous blood samples were drawn intoEDTA-containing tubes before the posaconazole dose on days 2, 5, 8, 12,and 15, and before the ranolazine dose on days 18, 22, 25, and 29. Oneadditional blood sample was taken 5 hours after the posaconazole dose onday 15 for approximate determination of maximum plasma posaconazoleconcentrations. Samples were centrifuged, and the plasma was separatedand frozen at −70° C. until the time of assay of plasma posaconazoleconcentrations.

Analytic Methods. All bioassay analysis was performed by KeystoneBioanalytical (North Wales, Pa.). For analysis of posaconazole, theinternal standard (posaconazole-d₄) was added to the biological samples.Plasma samples were precipitated using formic acid in acetonitrile andisolated using a Phree phospholipid removal tube, and then an aliquot ofthe sample was injected onto a high-pressure liquid chromatography withtandem mass spectrometry triple quadrupole mass spectrometer (SciexAPI-5500). The analytical column was a Unison CK-218, 3 m particle sizeHPLC column (50×2 mm) from Imtakt USA (Portland, Oreg.). The mobilephase consisted of an aqueous component (0.25% formic acid and 10 mmol/Lammonium formate in water) and an organic component (0.1% formic acid inacetonitrile) and was delivered by gradient, with the organic componentgoing from 35% to 100%. The m/z transitions monitored were 701.6→614.4for posaconazole and 705.6→618.4 for the internal standard. Thecalibration curve ranged from 1 to 1000 ng/mL (8 concentrations induplicate). The interassay precision of this method (as percentagecoefficient of variance) was 4.28% to 7.14%, and the interassay accuracy(as percentage relative error) was 7.02% to 3.12%.

For analysis of ranolazine in plasma samples, the internal standard(ranolazine-d3) was added to the biological samples. Plasma samples wereextracted by methyl tertiary butyl ether, centrifuged, and the upperlayer was transferred to plastic injection vials with MeOH/water(50:50). An aliquot of the sample was then injected onto a high-pressureliquid chromatography with tandem mass spectrometry triple quadrupolemass spectrometer (Sciex API-5500). The analytical column was a UnisonCK-218, 3 jm particle size HPLC column (50×2 mm) from Imtakt USA(Portland, Oreg.). The mobile phase consisted of an aqueous component(0.025% formic acid and 10 mmol/L ammonium formate in water) and organiccomponent (0.1% formic acid in acetonitrile) and was delivered bygradient, with the organic component going from 15% to 45%. The m/ztransitions monitored were 428.3→279.2 for ranolazine and 431.3→282.2for the internal standard. The calibration curve ranged from 5 to 2500ng/mL (8 concentrations in duplicate). The interassay precision of thismethod (as percentage coefficient of variance) was 1.49% to 40.8 8%, andthe intra-assay accuracy (as percentage relative error) was −30.07% to1.83%.

Pharmacokinetic and Statistical Methods. For each ranolazine trial ineach subject, the terminal log-linear phase of the plasma concentrationcurve was identified visually, and the terminal rate constant (β) wasdetermined by log-linear regression analysis. This was used to calculatethe half-life (t_(1/2)). The area under the plasma concentration curvefrom time 0 until the last nonzero point was determined by the lineartrapezoidal method. To this was added the residual area, calculated asthe final nonzero concentration divided by β, yielding the total areaunder the plasma concentration curve extrapolated to infinity (AUC).Also tabulated was the observed maximum plasma concentration (C_(max)).Variables were aggregated as arithmetic mean and SD. Ranolazine C_(max)and AUC were also aggregated as geometric mean and 90% CI.

For each subject, the predose plasma posaconazole concentration on studyday 15 was used as a steady-state concentration. The apparent washouthalf-life of posaconazole was calculated by log-linear regressionanalysis starting with the plasma concentration on day 15 and endingwith the last nonzero value. Differences between normal-weight and obesecohorts were evaluated by Student t-test for independent groups.

Differences in kinetic variables between study days 1 and 15, 18, 22,25, and 29 (control versus after posaconazole administration) wereevaluated either from the untransformed data using Dunnett's t-test orby comparison of geometric means and the 90% CI of the difference.

QTcF values were determined electronically from 12-lead ECG readingstaken for safety purposes. This protocol did not involve a thorough QTstudy; however, safety data were recorded, and the mean, standarddeviation, and standard error of QT and QTcF values were tabulated.Differences between baseline and study days 1, 15, and 30 were evaluatedby Student's t-test for independent groups.

Results. All 30 subjects completed day 1 of the study, and 27 completedthe full study protocol. (One subject was inadvertently given anincorrect dosage of study drug on day 1; this subject was allowed tore-enroll with a new subject number after an appropriate washoutperiod.) Two obese subjects and 1 normal-weight subject withdrew fromthe study before completion of all study procedures. In thenormal-weight group, 1 subject discontinued due to abdominal pain thatwas possibly related to ranolazine treatment. In the obese group, 1subject withdrew consent for personal reasons, and 1 subjectdiscontinued due to an adverse event (paresthesia) that was unrelated tothe study drug.

Obese subjects were similar in height to normal-weight subjects but weresignificantly higher in age, weight, BMI, and percentage of total bodyfat (Table 9).

TABLE 9 Demographic characteristics of study participants (mean ± SD)Normal-weight Obese Number 14 13 Age (years)  27.7 ± 10.6 33.9 ± 7.7Male/female 7/7 4/9 Weight (Kg) 71.2 ± 8.2 116.8 ± 19.6 (Pounds)   157 ±18.1 257.5 ± 43.2 Height (Cm) 174.0 ± 8.6  169.0 ± 11.8 (Inches) 68.5 ±3.4 66.5 ± 4.6 BMI (kg/m²) 23.5 ± 1.6 40.9 ± 5.7

Posaconazole plasma concentrations were lower in obese subjects than innormal-weight subjects (FIG. 5); however, this difference did not reachsignificance. This is consistent with previous observations of alteredposaconazole pharmacokinetics in obese subjects compared tonormal-weight subjects, where posaconazole plasma concentrations wereobserved to be lower in obese patients. Trough (predose) steady-stateposaconazole concentrations on day 15 were 3071±1422 ng/mL innormal-weight subjects and 2258±952 ng/mL in obese subjects.Surprisingly, however, it was also observed that the postdosage washouthalf-life of posaconazole in obese subjects was significantly increasedrelative to that in normal-weight subjects (64.3 hours and 35.8 hours,respectively). Posaconazole plasma concentrations persisted for at least2 weeks after stopping treatment in most subjects (FIG. 5).

The geometric mean AUC for ranolazine on day 1 was similar innormal-weight and obese subjects (6454 ng h/mL and 6955 ng h/mL,respectively). Similarly, the geometric mean C_(max) on day 1 did notdiffer significantly between groups (664.7±318.2 ng/mL and 559.1±270.7ng/mL in normal-weight and obese subjects, respectively). The geometricmean AUC and Cmax for ranolazine in both normal-weight and obesesubjects on days 15, 18, and 22 increased significantly compared to day1 (FIG. 6, Table 10). AUC and Cmax did not differ significantly betweengroups. t_(1/2) on day 1 was slightly prolonged in obese subjects(4.99±1.50 hours and 6.02±1.75 hours in normal-weight and obesesubjects, respectively), but this difference did not reach significance(P=0.126, Table 10).

TABLE 10 Pharmacokinetic parameters of ranolazine (mean ± SD)Normal-weight Obese Day 1 C_(max) (ng/mL) 665 ± 318 559 ± 271AUC_(0-inf) (ng/mL × h) 7085 ± 3603 8126 ± 4840 T_(1/2) (h)  4.98 ±1.50^(a)  6.02 ± 1.75^(a) Day 15 C_(max) (ng/mL) 1429 ± 666* 1177 ± 512*AUC_(0-inf) (ng/mL × h)  27477 ± 14895*  25842 ± 21638* T_(1/2) (h) 9.54± 4.3  8.78 ± 5.58 Day 18 C_(max) (ng/mL) 1188 ± 469* 1096 ± 502*AUC_(0-inf) (ng/mL × h)  17310 ± 10263*  19294 ± 14150* T_(1/2) (h) 5.73± 1.53 7.93 ± 2.98 Day 22 C_(max) (ng/mL)  974 ± 400* 1063 ± 508*AUC_(0-inf) (ng/mL × h) 13414 ± 6252*  15920 ± 11832* T_(1/2) (h) 6.47 ±3.14 6.09 ± 2.10 Day 25 C_(max) (ng/mL)  928 ± 482*  976 ± 487*AUC_(0-inf) (ng/mL × h) 9385 ± 4591 13846 ± 10600 T_(1/2) (h) 5.05 ±1.82 6.07 ± 2.10 Day 29 C_(max) (ng/mL) 751 ± 276 719 ± 333 AUC_(0-inf)(ng/mL × h) 8568 ± 3802 10171 ± 7942  T_(1/2) (h) 4.45 ±1.38  6.38±3.05  *Significance vs Day 1 determined by Dunnett's t-test ^(a)Notsignificant between normal-weight and obese groups (p = 0.126) byStudent's t-test

Within each cohort, the interaction between posaconazole and ranolazinewas greatest on day 15 relative to day 1 as determined by the AUCgeometric mean ratio (GMR) and 90% CI. The magnitude of the interactiondecreased from days 18 to 29; however, plasma ranolazine concentrationson day 29 were still increased relative to day 1 (FIG. 7, Table 11). Thelower bound of the AUC GMR 90% CI also remained above 1.0 for 7 days inboth normal-weight and obese subjects. Cmax GMRs and 90% CIs followed asimilar trend and can be found in Table 11.

TABLE 11 Geometric mean ratios (90% CI) of plasma ranolazineNormal-weight Obese Day 15/Day 1 AUC_(0-inf) 3.88 (2.94-5.13) 2.80(1.68-4.66) C_(max) 2.16 (1.61-2.87) 2.18 (1.55-3.04) Day 18/Day 1AUC_(0-inf) 2.34 (1.70-3.22) 2.25 (1.41-3.58) C_(max) 1.82 (1.38-2.42)1.97 (1.42-2.80) Day 22/Day 1 AUC_(0-inf) 1.88 (1.38-2.54) 1.79(1.11-2.88) C_(max) 1.50 (1.13-1.99) 1.90 (1.35-2.54) Day 25/Day 1AUC_(0-inf) 1.30 (0.97-1.76) 1.57 (0.99-2.50) C_(max) 1.36 (1.00-1.85)1.72 (1.20-2.47) Day 29/Day 1 AUC_(0-inf) 1.22 (0.92-1.62) 1.21(0.79-1.85) C_(max) 1.16 (0.89-1.53) 1.30 (0.94-1.82)

ECG data revealed that, on study day 30, the average change in QTcFinterval from screening values was 12.9±16 milliseconds in normal-weightsubjects who completed the study and 2.6±11 milliseconds in obesesubjects who completed the study (Table 12).

TABLE 12 QTcF values relative to baseline (msec, mean ± SD)Normal-weight Obese Day 1, predose 2.14 ± 10  7.50 ± 9.2 Day 1, 4 hpost-dose 9.85 ± 12 3.83 ± 11 Day 15, predose 6.29 ± 16 2.64 ± 11 Day15, 4 h post-dose 4.36 ± 16 −3.33 ± 13  Day 30 12.9 ± 16** 2.58 ± 11 **p= 0.012 compared to baseline

Discussion. The present study evaluated the effects of obesity on theplasma concentration of ranolazine in otherwise healthy adults during orafter cessation of posaconazole administration. Due to the known linearcorrelation between ranolazine plasma concentration and increases in theQTc interval, the lower marketed dose of 500 mg was chosen for testingin this study to minimize safety risks.

Without or during concomitant dosing of posaconazole, obese andnormal-weight subjects had similar C_(max), AUC, and t_(1/2) (Table 10).After cessation of posaconazole administration, both obese andnormal-weight subjects demonstrated persistence of elevated ranolazinelevels for several days. Interestingly, the t_(1/2) of ranolazineincreased slightly with the magnitude of the interaction. The magnitudeof the effect of posaconazole on day 15 C_(max) was similar betweennormal-weight and obese subjects (C_(max) GMR=2.16 and 2.18,respectively). The interaction persisted above a C_(max) GMR of 1.5 for7 and 10 days in normal-weight and obese subjects, respectively. Themagnitude of the interaction on day 15 AUC was greater in normal-weightsubjects than in obese subjects (AUC GMR, day 15/day 1=3.88 and 2.90,respectively). After day 15, however, the magnitude of the interactionwas similar in obese and normal-weight subjects and decreased asposaconazole was eliminated from the body (FIG. 7). The interactionbetween ranolazine and residual posaconazole persisted above an AUC GMRof 1.5 for at least 7 and 10 days after cessation of posaconazoleadministration in normal-weight and obese subjects, respectively.

C_(max) and AUC GMRs of 1.5 were also observed in preapproval drug-druginteraction studies between ranolazine and diltiazem, a moderate CYP3Ainhibitor.

Based on the results of these preapproval studies, current prescribinginstructions for ranolazine state that the maximum dosage of ranolazineshould be limited to 500 mg twice a day when taken concomitantly withmoderate CYP3A inhibitors, and ranolazine is contraindicated forconcomitant use with strong CYP3A inhibitors such as posaconazole. Thesedosing recommendations are based on the linear correlation betweenranolazine plasma concentrations and QT interval because risk of cardiacarrhythmias increases as the QT interval increases.

Among the 27 subjects who completed this study, an average increase inthe QTcF interval of 12.9 milliseconds was observed in normal-weightpatients on day 30 compared to screening. The average QTcF interval inobese subjects was 2.6 milliseconds. The increase of 12.9 millisecondsin normal subjects was statistically significant (P=0.012) (Table 12).The changes in QTcF were observed from safety ECG data and were notderived from a thorough QT study; however, given current FDA guidance onQT-prolonging drugs, it is important to note this finding.

This study is one of the first reports of a sustained drug-druginteraction with posaconazole. Although time-dependent inhibition ofCYP3A by posaconazole is minimal, the results of these studies suggestthat inhibition of CYP3A by posaconazole persists after cessation ofadministration and should be accounted for in clinical practice.

In current clinical practice, a patient on ranolazine in need oftreatment with posaconazole would stop taking ranolazine while beingtreated with posaconazole, and then resume ranolazine shortly afterfinishing the posaconazole regimen to recommence treatment for chronicangina. The results of this study suggest that physicians shouldinstruct their patients to delay/limit the dose of ranolazine for anextended period after stopping posaconazole to avoid drug-druginteractions due to residual posaconazole levels.

Conclusion. Posaconazole, a known CYP3A strong inhibitor, increasesranolazine concentrations to a clinically relevant and potentiallyhazardous extent during concomitant administration and for several daysfollowing its discontinuation. Although steady-state posaconazoleconcentrations are lower in obese subjects than in normal-weightsubjects, its half-life is increased in obese subjects such that thepersistence of the interaction is observed in both obese andnormal-weight people. The magnitude of the interaction betweenranolazine and residual posaconazole elevates ranolazine plasmaconcentrations to the extent that they are at risk for significant QTcprolongation and potentially fatal cardiac arrhythmias. Based on theresults of this study, administration of ranolazine should be limited to500 mg twice daily for 7 days after posaconazole discontinuation inpatients with BMI 18.5-24.9 kg/m² and for 12 days in patients withBMI≥35 kg/m² after ranolazine is resumed.

1. A method of treating a patient in need thereof with a CYP3A4substrate drug, wherein the patient is treated with posaconazole,comprising the steps of: (a) selecting a reference dose of the CYP3A4substrate drug based on the patient's age and/or condition; (b) stoppingposaconazole treatment; (c) waiting at least two days after stoppingposaconazole treatment; and then (d) administering the CYP3A4 substratedrug as soon as it is safe.
 2. The method of claim 1, wherein the CYP3A4substrate drug is selected from the group consisting of lurasidone,ranolazine, lumacaftor/ivacaftor, venetoclax, trabectedin, ribociclibsuccinate, deflazacort, cinacalcet hydrochloride, pimavanserin tartrate,aripiprazole lauroxil, cariprazine hydrochloride, simeprevir sodium,everolimus, saxagliptin hydrochloride, saxagliptin/metforminhydrochloride, ticagrelor, vilazodone hydrochloride, apixaban,tofacitinib citrate, eletriptan hydrobromide, nilotinib hydrochloridemonohydrate, dronedarone hydrochloride, fluticasonepropionate/salmeterol xinafoate, rivaroxaban, tadalafil, ibrutinib,cobimetinib, colchicine, cabazitaxel, tolvaptan, fosaprepitantdimeglumine, aprepitant, solifenacin succinate, erlotinib hydrochloride,ado-trastuzumab ematansine, bosutinib monohydrate, sunitinib malate,fesoterodine fumarate, maraviroc, pazopanib hydrochloride, aripiprazole,axitinib, dapagliflozin/saxagliptin, cabozantinib S-malate, ponatinibhydrochloride, isavucazonium sulfate, lomitapide mesylate, iloperidone,palbociclib, levomilacipran hydrochloride, pimozide, pomalidomide,abemaciclib, ivacaftor, olaparib, ruxolitinib phosphate, brexpiprazole,ivacaftor/tezacaftor, regorafenib, daclatasvir, crizotinib, naloxegoloxalate, dabrafenib, elbasvir/grazoprevir, apalutamide, brigatinib,cannabidiol, copanlisib, duvelisib, encorafenib, flibanserin,ivabradine, ivosidenib, panobinostat, sonidegib, and vemurafenib:
 3. Themethod of claim 1, wherein the CYP3A4 substrate drug is selected fromthe group consisting of lumacaftor/ivacaftor, venetoclax, trabectedin,ribociclib succinate, deflazacort, cinacalcet hydrochloride,pimavanserin tartrate, aripiprazole lauroxil, cariprazine hydrochloride,simeprevir sodium, everolimus, saxagliptin hydrochloride,saxagliptin/metformin hydrochloride, ticagrelor, vilazodonehydrochloride, apixaban, tofacitinib citrate, eletriptan hydrobromide,nilotinib hydrochloride monohydrate, dronedarone hydrochloride,fluticasone propionate/salmeterol xinafoate, rivaroxaban, tadalafil,ibrutinib, cobimetinib, colchicine, cabazitaxel, tolvaptan,fosaprepitant dimeglumine, aprepitant, solifenacin succinate, erlotinibhydrochloride, ado-trastuzumab ematansine, bosutinib monohydrate,sunitinib malate, fesoterodine fumarate, maraviroc, pazopanibhydrochloride, aripiprazole, axitinib, dapagliflozin/saxagliptin,cabozantinib S-malate, ponatinib hydrochloride, isavucazonium sulfate,lomitapide mesylate, iloperidone, palbociclib, levomilacipranhydrochloride, pimozide, pomalidomide, abemaciclib, ivacaftor, olaparib,ruxolitinib phosphate, brexpiprazole, ivacaftor/tezacaftor, regorafenib,daclatasvir, crizotinib, naloxegol oxalate, dabrafenib,elbasvir/grazoprevir, apalutamide, brigatinib, cannabidiol, copanlisib,duvelisib, encorafenib, flibanserin, ivabradine, ivosidenib,panobinostat, sonidegib, and vemurafenib.
 4. The method of claim 1,wherein the CYP3A4 substrate drug is selected from the group consistingof cabazitaxel, tolvaptan, fosaprepitant dimeglumine, aprepitant,solifenacin succinate, erlotinib hydrochloride, ado-trastuzumabematansine, bosutinib monohydrate, sunitinib malate, fesoterodinefumarate, maraviroc, pazopanib hydrochloride, aripiprazole, axitinib,dapagliflozin/saxagliptin, cabozantinib S-malate, ponatinibhydrochloride, isavucazonium sulfate, lomitapide mesylate, iloperidone,palbociclib, levomilacipran hydrochloride, pimozide, pomalidomide,abemaciclib, ivacaftor, olaparib, ruxolitinib phosphate, brexpiprazole,ivacaftor/tezacaftor, regorafenib, daclatasvir, crizotinib, naloxegoloxalate, dabrafenib, elbasvir/grazoprevir, apalutamide, brigatinib,cannabidiol, copanlisib, duvelisib, encorafenib, flibanserin,ivabradine, ivosidenib, panobinostat, sonidegib, and vemurafenib.
 5. Themethod of claim 1, wherein the CYP3A4 substrate drug is selected fromthe group consisting of cabazitaxel, tolvaptan, fosaprepitantdimeglumine, aprepitant, solifenacin succinate, erlotinib hydrochloride,ado-trastuzumab ematansine, bosutinib monohydrate, sunitinib malate,fesoterodine fumarate, maraviroc, pazopanib hydrochloride, aripiprazole,axitinib, dapagliflozin/saxagliptin, cabozantinib S-malate, ponatinibhydrochloride, isavucazonium sulfate, lomitapide mesylate, iloperidone,palbociclib, levomilacipran hydrochloride, pimozide, and pomalidomide.6. The method of claim 1, wherein the CYP3A4 substrate drug is selectedfrom the group consisting of abemaciclib, ivacaftor, olaparib,ruxolitinib phosphate, brexpiprazole, ivacaftor/tezacaftor, regorafenib,daclatasvir, crizotinib, naloxegol oxalate, dabrafenib, andelbasvir/grazoprevir.
 7. The method of claim 1, wherein the CYP3A4substrate drug is selected from the group consisting of apalutamide,brigatinib, cannabidiol, copanlisib, duvelisib, encorafenib,flibanserin, ivabradine, ivosidenib, panobinostat, sonidegib, andvemurafenib.
 8. The method of claim 1, wherein the CYP3A4 substrate drugis administered in step (d) as soon as at least one of the AUC, Cmax,GMR AUC, or GMR Cmax of the CYP3A4 substrate does not exceed a maximumlevel where benefits of treating the patient outweigh risks of elevatedexposure to the CYP3A4 substrate drug.
 9. The method of claim 1, whereinthe CYP3A4 substrate drug is administered in step (d) as soon as atleast one of the AUC, Cmax, GMR AUC, or GMR Cmax of the CYP3A4 substratedrug does not exceed a target safe level listed in Table A for theCYP3A4 substrate drug.
 10. The method of claim 1, wherein the CYP3A4substrate drug is administered in step (d) to achieve an AUC or Cmax ofthe CYP3A4 substrate that is at least about 105% of an expected AUC orCmax for the day on which that CYP3A4 substrate drug is administered.11. The method of claim 10, wherein the an AUC or Cmax of the CYP3A4substrate that is at least about 105% of a predicted AUC or Cmax for theday on which that CYP3A4 substrate drug is administered but no more thana target safe level disclosed in Table A for the CYP3A4 substrate drug.12. The method of claim 1, wherein the CYP3A4 substrate drug isadministered in step (d) achieve a GMR AUC or GMR Cmax of the CYP3A4substrate drug that is at least about 1.05 fold of the expected AUC orCmax.
 13. The method of claim 12, wherein the CYP3A4 substrate drug isadministered in step (d) achieve a GMR AUC or GMR Cmax of the CYP3A4substrate drug that is at least about 1.05 fold of the predicted AUC orCmax for the day on which that CYP3A4 substrate drug is administered butno more than a target safe level disclosed in Table A for the CYP3A4substrate drug.
 14. The method of claim 1, wherein the waiting in step(c) is at least 5 days.
 15. The method of claim 1, wherein the waitingin step (c) is at least 7 days.
 16. The method of claim 1, wherein thewaiting in step (c) is at least 14 days.
 17. The method claim 1, whereinthe waiting in step (c) is in the range of from 2-42 days.
 18. Themethod of claim 1, wherein the waiting in step (c) is in the range offrom 5-42 days.
 19. The method of claim 1, wherein the waiting in step(c) is in the range of from 7-21 days.
 20. The method of claim 1,wherein the waiting in step (c) is in the range of from 14-28 days 21.The method of claim 1, wherein the patient is treated for a disease orcondition selected from the group consisting of schizophrenia in adultsand adolescents (13 to 17 years), depressive episodes associated withBipolar I Disorder (bipolar depression) in adults and pediatric patients(10-17 years) as monotherapy or adjunctive therapy with lithium orvalproate, moderate bipolar depression, severe bipolar depression, andsevere bipolar depression with acute suicidal idealation and behavior(ASIB), chronic angina, cystic fibrosis in patients 6 years and olderwho are homozygous for the F508del mutation in the CFTR gene, chroniclymphocytic leukemia in patients with 17p deletion, who have received atleast one prior therapy, unresectable or metastatic liposarcoma orleiomyosarcoma in patients who received a prior anthracycline-containingregimen, advanced or metastatic breast cancer in postmenopausal womenwith hormone receptor (HR)-positive, human epidermal growth factorreceptor 2 (HER2)-negative advanced or metastatic breast cancer,negative advanced or metastatic breast cancer in combination with anaromatase inhibitor for postmenopausal women, Duchenne musculardystrophy (DMD), secondary hyperparathyroidism (HPT) in patients withchronic kidney disease (CKD) on dialysis, hypercalcemia in patients withparathyroid carcinoma or in patients with primary HPT for whoparathyroidectomy would be indicated on the basis of serum calciumlevels, but who are unable to undergo parathyroidectomy, hallucinationsand delusions associated with Parkinson's disease psychosis,schizophrenia, acute manic or mixed episodes associated with bipolar Idisorder, chronic hepatitis C (CHC) infection as a component of acombination antiviral treatment regimen with peginterferon alfa andribavirin in HCV genotype 1 infected subjects with compensated liverdisease, postmenopausal women with advanced hormone receptor-positive,HER2-negative breast cancer (advanced HR+BC), e.g., in combination withexemestane after failure of treatment with letrozole or anastrozole,progressive neuroendocrine tumors of pancreatic origin (PNET),progressive, well-differentiated, non-functional neuroendocrine tumors(NET) of gastrointestinal (GI) or lung origin that are unresectable,locally advanced or metastatic, advanced renal cell carcinoma (RCC),e.g., after failure of treatment with sunitinib or sorafenib, renalangiomyolipoma and tuberous sclerosis complex (TSC), not requiringimmediate surgery, TSC in patients who have subependymal giant cellastrocytoma (SEGA) that require therapeutic intervention but are notcandidates for surgical resection, type 2 diabetes mellitus in adults asan adjunct to diet and exercise to improve glycemic control, majordepressive disorder (MDD), thrombotic cardiovascular events (e.g.,cardiovascular death, myocardial infarction, or stroke) in patients withacute coronary syndrome (ACS), stroke and systemic embolism in patientswith nonvalvular atrial fibrillation, deep vein thrombosis (DVT), whichmay lead to pulmonary embolism (PE) in patients who have undergone hipor knee replacement surgery, DVT, PE, recurrent DVT and PE followinginitial therapy, moderate to severe active rheumatoid arthritis inpatients who have had inadequate response or tolerance to methotrexate,acute migraine with or without aura, chronic phase and accelerated phasePhiladelphia chromosome positive chronic myeloid leukemia (Ph+ CML) innewly diagnosed patients or in patients resistant to or intolerant toprior therapy that included imatinib, atrial fibrillation (AF) inpatients with a history of paroxysmal or persistant AF or atrial flutter(AFK), who are in sinus rhythm or will be cardioverted, asthma inpatients aged 4 years and older, airflow obstruction and reducingexacerbations in patients with chronic obstructive pulmonary disease,erectile dysfunction (ED), benign prostatic hyperplasia (BPH), pulmonaryarterial hypertension (PAH) (WHO Group 1) to improve exercise ability,gout flares, Familial Mediterranean fever, antiretroviral therapy,anxiety disorders, panic disorders, seizures, insomnia, hypertension,cardiovascular disease, hyperlipidemia, cancer, such as primary kidneycancer, advanced primary liver cancer, radioactive iodine resistantadvanced thyroid carcinoma, renal cell carcinoma, imatinib-resistantgastrointestinal stromal tumor, mantle cell lymphoma in patients whohave received at least one prior therapy, chronic lymphocyticleukemia/small lymphocytic lymphoma, chronic lymphocytic leukemia/smalllymphocytic lymphoma with 17p deletion, Waldenström's macroglobulinemia,marginal zone lymphoma who require systemic therapy and have received atleast one prior anti-CD20-based therapy, unresectable or metastaticmelanoma with a BRAF V600E or V600K mutation, allergies,transplantation, hormone-refractory metastatic prostate cancerpreviously treated with a docetaxel-containing treatment regimen,hormone-refractory metastatic prostate cancer previously treated with adocetaxel-containing treatment regimen, treatment of clinicallysignificant hypervolemic and euvolemic hyponatremia, including patientswith heart failure and Syndrome of Inappropriate Antidiuretic Hormone(SIADH), prevention of acute and delayed nausea and vomiting associatedwith initial and repeat courses of highly emetogenic cancer chemotherapy(HEC) including high-dose cisplatin, prevention of delayed nausea andvomiting associated with initial and repeat courses of moderatelyemetogenic cancer chemotherapy (MEC), over-active bladder with symptomsof urge urinary incontinence, urgency, and urinary frequency, metastaticnon-small cell lung cancer (NSCLC) whose tumors have epidermal growthfactor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitutionmutations as detected by an FDA-approved test receiving first-line,maintenance, or second or greater line treatment after progression,locally advanced, unresectable or metastatic pancreatic cancer, incombination with gemcitabine, HER2-positive, metastatic breast cancerwho previously received trastuzumab and a taxane, separately or incombination in patients who have either: received prior therapy formetastatic disease or developed disease recurrence during or within sixmonths of completing adjuvant therapy, chronic, accelerated, or blastphase Ph+ chronic myelogenous leukemia (CML) in adults with resistanceor intolerance to prior therapy, gastrointestinal stromal tumor (GIST)after disease progression on or intolerance to imatinib mesylate,advanced renal cell carcinoma (RCC), progressive, well-differentiatedpancreatic neuroendocrine tumors (pNET) in patients with unresectablelocally advanced or metastatic disease, CCR5-tropic HIV-1 infection inpatients 2 years of age and older weighing at least 10 kg in combinationwith other antiretroviral agents, advanced renal cell carcinoma,advanced soft tissue sarcoma who have received prior chemotherapy, manicand mixed episodes associated with Bipolar I, Major Depressive Disorder,irritability associated with Autistic Disorder, Tourette's disorder,agitation associated with schizophrenia or bipolar mania, advanced renalcell carcinoma after failure of one prior systemic therapy, to improveglycemic control in adults with type 2 diabetes mellitus (T2DM) who haveinadequate control with dapagliflozin or who are already treated withdapagliflozin and saxagliptin, progressive, metastatic medullary thyroidcancer (MTC), advanced renal cell carcinoma (RCC) who have receivedprior anti-angiogenic therapy, chronic phase, accelerated phase, orblast phase chronic myeloid leukemia (CML) or Ph+ ALL in adults for whomno other tyrosine kinase inhibitor (TKI) therapy is indicated,T315I-positive CML (chronic phase, accelerated phase, or blast phase) orT315I-positive Philadelphia chromosome in adults, positive acutelymphoblastic leukemia (Ph+ ALL), invasive aspergillosis, invasivemucormycosis, to reduce low-density lipoprotein cholesterol (LDL-C),total cholesterol (TC), apolipoprotein B (apo B), and non-high densitylipoprotein cholesterol (non-HDL-C) in patients with homozygous familialhypercholesterolemia (HoFH), schizophrenia in adults, hormone receptor(HR)-positive, human epidermal growth factor receptor 2 (HER2)-negativeadvanced or metastatic breast cancer in combination with an aromataseinhibitor as initial endocrine based therapy in postmenopausal women, orfulvestrant in women with disease progression following endocrinetherapy, Major Depressive Disorder (MDD), suppression of motor andphonic tics in patients with Tourette's Disorder who have failed torespond satisfactorily to standard treatment, treatment of multiplemyeloma in patients who have received at least two prior therapiesincluding lenalidomide and a proteasome inhibitor and have demonstrateddisease progression on or within 60 days of completion of the lasttherapy, non-small cell lung cancer (NSCLC) whose disease has notprogressed after four cycles of platinum-based first-line chemotherapy,locally advanced or metastatic NSCLC after failure of at least one priorchemotherapy regimen, locally advanced, unresectable or metastaticpancreatic cancer, overactive bladder with symptoms of urge urinaryincontinence, urgency, and urinary frequency, advanced renal cellcarcinoma (RCC) after failure of treatment with sunitinib or sorafenib,subependymal giant cell astrocytoma (SEGA) associated with tuberoussclerosis (TS) who require therapeutic intervention but are notcandidates for curative surgical resection, renal angiomyolipoma,tuberous sclerosis complex, hormone receptor (HR)-positive, humanepidermal growth factor receptor 2 (HER2)-negative advanced ormetastatic breast cancer with disease progression following endocrinetherapy in women in combination with fulvestrant, as monotherapy for thetreatment of adult patients with HRpositive, HER2-negative advanced ormetastatic breast cancer with disease progression following endocrinetherapy and prior chemotherapy in the metastatic setting, cysticfibrosis (CF) in patients age 2 years and older who have one mutation inthe CFTR gene that is responsive to ivacaftor based on clinical and/orin vitro assay data, deleterious or suspected deleterious germlineBRCA-mutated advanced ovarian cancer in adult patients who have beentreated with three or more prior lines of chemotherapy, intermediate orhigh-risk myelofibrosis, including primary myelofibrosis,post-polycythemia vera myelofibrosis and post-essential thrombocythemiamyelofibrosis, polycythemia vera patients who have had an inadequateresponse to or are intolerant of hydroxyurea, as an adjunctive therapyto antidepressants for the treatment of major depressive disorder (MDD),schizophrenia, cystic fibrosis (CF) patients aged 12 years and older whoare homozygous for the F508del mutation or who have at least onemutation in the cystic fibrosis transmembrane conductance regulator(CFTR) gene that is responsive to tezacaftor/ivacaftor based on in vitrodata and/or clinical evidence, metastatic colorectal cancer (CRC)patients who have been previously treated with fluoropyrimidine-,oxaliplatin- and irinotecan-based chemotherapy, an antiVEGF therapy,and, if RAS wild-type, an anti-EGFR therapy, locally advanced,unresectable or metastatic gastrointestinal stromal tumor (GIST)patients who have been previously treated with imatinib mesylate andsunitinib malate, hepatocellular carcinoma (HCC) who have beenpreviously treated with sorafenib, chronic HCV genotype 1 or 3 infectionwith sofosbuvir and with or without ribavirin, metastatic non-small celllung cancer (NSCLC) in patients whose tumors are anaplastic lymphomakinase (ALK) or ROS1-positive as detected by an FDA-approved test,opioid induced constipation (OIC) in adult patients with chronicnon-cancer pain, including patients with chronic pain related to priorcancer or its treatment who do not require frequent (e.g., weekly)opioid dosage escalation, unresectable or metastatic melanoma inpatients with BRAF V600E mutation as detected by an FDA-approved test,in combination with trametinib, for the treatment of unresectable ormetastatic melanoma in patients with BRAF V600E or V600K mutations asdetected by an FDA-approved test, melanoma in patients with BRAF V600Eor V600K mutations, as detected by an FDA-approved test, and involvementof lymph node(s), following complete resection, metastatic non-smallcell lung cancer (NSCLC) in patients with BRAF V600E mutation asdetected by an FDA-approved test, locally advanced or metastaticanaplastic thyroid cancer (ATC) in patients with BRAF V600E mutation andwith no satisfactory locoregional treatment options, with or withoutribavirin for treatment of chronic HCV genotypes 1 or 4 infection inadults, the treatment of patients with non-metastaticcastration-resistant prostate cancer, the treatment of patients withanaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lungcancer (NSCLC) who have progressed on or are intolerant to crizotinib,the treatment of seizures associated with Lennox-Gastaut syndrome orDravet syndrome in patients 2 years of age and older, the treatment ofadult patients with relapsed follicular lymphoma (FL) who have receivedat least two prior systemic therapies, the treatment of adult patientswith relapsed or refractory chronic lymphocytic leukemia (CLL) or smalllymphocytic lymphoma (SLL) after at least two prior therapies, thetreatment of adult patients with relapsed or refractory follicularlymphoma (FL) after at least two prior systemic therapies, incombination with binimetinib, for the treatment of patients withunresectable or metastatic melanoma with a BRAF V600E or V600K mutation,as detected by an FDA-approved test, the treatment of premenopausalwomen with acquired, generalized hypoactive sexual desire disorder(HSDD) as characterized by low sexual desire that causes marked distressor interpersonal difficulty and is not due to a co-existing medical orpsychiatric condition, problems within the relationship, or the effectsof a medication or other drug substance, to reduce the risk ofhospitalization for worsening heart failure in patients with stable,symptomatic chronic heart failure with left ventricular ejectionfraction ≤35%, who are in sinus rhythm with resting heart rate ≥70 beatsper minute and either are on maximally tolerated doses of beta-blockersor have a contraindication to beta-blocker use, the treatment of adultpatients with relapsed or refractory acute myeloid leukemia (AML) with asusceptible IDH1 mutation as detected by an FDA-approved test, thetreatment of patients with multiple myeloma who have received at least 2prior regimens, including bortezomib and an immunomodulatory agent, thetreatment of adult patients with locally advanced basal cell carcinoma(BCC) that has recurred following surgery or radiation therapy, or thosewho are not candidates for surgery or radiation therapy, the treatmentof patients with unresectable or metastatic melanoma with BRAF V600Emutation as detected by an FDA-approved test, and the treatment ofpatients with Erdheim-Chester Disease with BRAF V600 mutation.
 22. Themethod of claim 1, wherein the patient is treated for a disease orcondition selected from the group consisting of: non-metastaticcastration-resistant prostate cancer; anaplastic lymphoma kinase(ALK)-positive metastatic non-small cell lung cancer (NSCLC) who haveprogressed on or are intolerant to crizotinib; seizures associated withLennox-Gastaut syndrome or Dravet syndrome in patients 2 years of ageand older; relapsed follicular lymphoma (FL) in adults who have receivedat least two prior systemic therapies; adults with relapsed orrefractory chronic lymphocytic leukemia (CLL) or small lymphocyticlymphoma (SLL) after at least two prior therapies; adult patients withrelapsed or refractory follicular lymphoma (FL) after at least two priorsystemic therapies, in combination with binimetinib; unresectable ormetastatic melanoma with a BRAF V600E or V600K mutation, as detected byan FDA-approved test, the treatment of premenopausal women withacquired, generalized hypoactive sexual desire disorder (HSDD) ascharacterized by low sexual desire that causes marked distress orinterpersonal difficulty and is not due to a co-existing medical orpsychiatric condition, problems within the relationship, or the effectsof a medication or other drug substance, to reduce the risk ofhospitalization for worsening heart failure in patients with stable,symptomatic chronic heart failure with left ventricular ejectionfraction ≤35%, who are in sinus rhythm with resting heart rate ≥70 beatsper minute and either are on maximally tolerated doses of beta-blockersor have a contraindication to beta-blocker use; adult patients withrelapsed or refractory acute myeloid leukemia (AML) with a susceptibleIDH1 mutation as detected by an FDA-approved test; multiple myeloma whohave received at least 2 prior regimens, including bortezomib and animmunomodulatory agent; adult patients with locally advanced basal cellcarcinoma (BCC) that has recurred following surgery or radiationtherapy, or those who are not candidates for surgery or radiationtherapy; unresectable or metastatic melanoma with BRAF V600E mutation asdetected by an FDA-approved test; Erdheim-Chester Disease with BRAF V600mutation; non-metastatic castration-resistant prostate cancer;anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lungcancer (NSCLC) who have progressed on or are intolerant to crizotinib;seizures associated with Lennox-Gastaut syndrome or Dravet syndrome inpatients 2 years of age and older; adult patients with relapsedfollicular lymphoma (FL) who have received at least two prior systemictherapies; adult patients with relapsed or refractory chroniclymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) after atleast two prior therapies; adult patients with relapsed or refractoryfollicular lymphoma (FL) after at least two prior systemic therapies, incombination with binimetinib, for the treatment of patients withunresectable or metastatic melanoma with a BRAF V600E or V600K mutation,as detected by an FDA-approved test; premenopausal women with acquired,generalized hypoactive sexual desire disorder (HSDD) as characterized bylow sexual desire that causes marked distress or interpersonaldifficulty and is not due to a co-existing medical or psychiatriccondition, problems within the relationship, or the effects of amedication or other drug substance; to reduce the risk ofhospitalization for worsening heart failure in patients with stable,symptomatic chronic heart failure with left ventricular ejectionfraction ≤35%, who are in sinus rhythm with resting heart rate ≥70 beatsper minute and either are on maximally tolerated doses of beta-blockersor have a contraindication to beta-blocker use; adult patients withrelapsed or refractory acute myeloid leukemia (AML) with a susceptibleIDH1 mutation as detected by an FDA-approved test; patients withmultiple myeloma who have received at least 2 prior regimens, includingbortezomib and an immunomodulatory agent, the treatment of adultpatients with locally advanced basal cell carcinoma (BCC) that hasrecurred following surgery or radiation therapy, or those who are notcandidates for surgery or radiation therapy; patients with unresectableor metastatic melanoma with BRAF V600E mutation as detected by anFDA-approved test; and the treatment of patients with Erdheim-ChesterDisease with BRAF V600 mutation.